lewis, neil (1995) asymmetric piperidine synthesis. phd...
TRANSCRIPT
Lewis, Neil (1995) Asymmetric piperidine synthesis. PhD thesis, University of Nottingham.
Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/13293/1/283603.pdf
Copyright and reuse:
The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.
This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
For more information, please contact [email protected]
"Asymmetric Piperidine Synthesis"
Neil Lewis, BSc
Thesis submitted to the University of Nottingham
for the degree of Doctor of Philosophy, June 1995.
Contents
Chapter 1 The use of Bakers' Yeast in Enantioselective Synthesis 1
Introduction to bakers' yeast 2
Reactions of bakers' yeast
(1) The stereoselective reduction of ~-keto esters 4
(2) The stereoselective reduction of a-keto esters 16
and a-keto acids
(3) The stereoselective reduction of 1,2 and 1,3 20
diketones
(4) The stereoselective reduction of 4 and 5- 22
oxoalkanoic acids and esters
(5) The stereos elective reduction of carbon-carbon 22
double bonds
(6) Carbon-carbon bond formation reactions 25
Enhancement of chemical yield and enantioselectivity in 31
bakers' yeast mediated reactions
(A) Addition of a third reagent to the reaction system 31
(B) Immobilisation of the cellular mass 34
(C) Substrate concentration 37
Chapter 2 Preparation and yeast reduction of the piperidine derivatives 39
Preparation of the piperidine derivatives 40
Yeast reduction of the piperidine derivatives 48
Chapter 3 Synthesis of (R)-3-Quinuclidinol 66
Introduction to Quinuclidines 67
Synthesis of (R )-3-Quinuclidinol 80
Chapter 4 Indolizidine Alkaloid Synthesis 97
Introduction to Indolizidines 98
Castanospermine 99
Swainsonine 107
Allupumiliotoxin 339A 113
Cyclizidine 116
Synthesis of 1-acetoxy-2-hydroxy-3-(hydroxymethyl)- 119
indolizidine
Chapter 5 Experimental 127
References 177
Publication 192
Abstract
It has been demonstrated that bakers' yeast reduction of 1-tert-butyl-2-methyl
3-oxo-piperidine-1,2-dicarboxylate gtves (2R,35), 1-tert-butyl-2-methyI3-
hydroxy-piperidine-1,2-dicarboxylate in 80% chemical yield with >99% d.e. and
>97% e.e. Also bakers' yeast reduction of 1-tert-butyl-3-ethyl 4-oxo-piperidine-
1,3-dicarboxylate gives (3R, 45), 1-tert-butyl-3-ethyI4-hydroxy-piperidine-1,3-
dicarboxylate in 74% chemical yield with >99% d.e. and >93% e.e. The optical
purity and absolute configurations of the hydroxy-ester derivatives were
determined by conversion into the corresponding chiral bis-tosylate
derivatives of 2- and 3-piperidinemethanol respectively.
It has also been shown that bakers' yeast reduction of 1-tert-butyl-4-methyl 3-
oxo-piperidine-1,4-dicarboxylate gives (3R, 4R)-l-tert-butyl-4-methyl 3-hydroxy
piperidine-dicarboxylate in 81% chemical yield with >99% d.e. and 87% e.e.
The optical purity and absolute configuration of the hydroxy-ester derivative
were determined by utilisation of the compound in the total synthesis of (R )-3-
quinuclidinol via chain elongation at C-4 of the piperidine followed by
cyclisation to produce the bicyclic structure.
Further work IS reported on the diastereoselective synthesis of
polyhydroxylated indolizidine alkaloids. 1-Acetoxy-2-hydroxy-3-
(hydroxymethyl)-indolizidine has been synthesised as a single diastereomer
from 2-piperidinemethanol via attack of an amine onto an epoxide
functionality thus producing the bicyclic system.
Dedication
To Mum and Dad
Acknowledgements
I would like to express my sincere thanks to my supervisor Dr. D. W. Knight
and my industrial supervisor, Dr. D. Haigh, for their invaluable contributions
during the course of this work. I would also like to express my thanks to the
technical staff at Nottingham University and SB Pharmaceuticals, Great
Burgh, for their assistance throughout this time. I acknowledge SB
Pharmaceuticals and the Science and Engineering Research Council for
financial support through the CASE scheme.
Declaration
I hereby declare that the substance of this thesis has not been nor is being
currently submitted in candidature for any other degree.
I also declare that the work embodied in this thesis is the result of my own
investigations and where work of other investigators has been used this is
fully acknowledged in the text.
(Neil Lewis)
DIRECTOR OF STUDY
(Dr. D. W. Knight)
Abbreviations used in the text
Ac Acetyl
AIBN Azo-bis-isobutyronitrile
Bn Benzyl
BOC t-Butyl carbonate
Bu Butyl
BY Bakers' yeast
COl 1,1' -Carbonyldiimidazole
DBU 1,S-diazobicyclo[ 5.4.0 ]undecene-7
DBY Dried bakers' yeast
OC'C Dicyclohexylcarbodiimide
d.e. Diasteromeric excess
DEAD Diethylazodicarboxylate
DIBAL-H Diisobutylaluminium hydride
DMAP 4-Dimethy laminopyridine
DMF Dimethy lformamide
DMSO Dimethy lsul phoxide
e.e. Enantiomeric excess
Et Ethyl
1m Imidazole
IMBY Immobilised bakers' yeast
LDA Lithi urn diisopropy lamine
mCPBA m-Chloroperoxybenzoic acid
Me Methyl
MOM Methoxymethy I
Ms Methane sulphonyl
NMR Nuclear magnetic resonance
NOE Nuclear Overhauser Effect
Ph Phenyl
Pr Propyl
TBDMS t-Butyldimethylsilyl
TBDPS t-Butyldiphenylsilyl
Tf CF3S02
TFA Trifluoroacetic acid
THF Tetrahydrofuran
Ts p-Toluene sulphonyl
TMS Trimethylsilyl / Tetramethylsilane
Z Benzyl carbonate
Chapter One
The use of Bakers' Yeast in Enantioselective Synthesis
1
Introduction to bakers' yeast
In the past few years a growing interest in chiral compounds arose in synthetic
organic chemistry. This interest has in the main been fuelled by the pressure that
has been put on the pharmaceutical industry to produce enantiomerically pure
drugs since unwanted enantiomers can in theory have harmful and sometimes
fatal effects. The use of naturally occurring chiral building blocks has been known
for quite some time and indeed sugars and amino acids are commonplace chiral
compounds used in enantioselective synthesis. The so called 'chiral pool' which is
a selection of readily available chiral compounds is increasing in size, which
makes for a wide choice of chiral building blocks for the organic chemist
interested in enantioselective synthesis.
Accompanying the growth of the chiral pool has been a surge in the amount of
scientific papers appearing in the literature regarding stereo- and enantioselective
transformations. Indeed comprehensive reviews have been written on general
areas of stereoselective transformations such as enantioselective addition of
titanium compounds to carbonyl groups,! addition of organozinc compounds to
aldehydes2 and asymmetric conjugate addition3 to name but three. During the
same time, synthetic organic chemists have appreciated the input received from
microbiologists and indeed microbial and enzymatic mediated transformations are
becoming increasingly popular in the laboratory.
The chemists desire to satisfy the hunger for chirality has led to a revived interest
In bakers' yeast (Saccharomyces cerevisiae) mediated stereoselective
transformations4. The use of bakers yeast as a laboratory reagent was reported
nearly a century agoS,6 and by the mid 1950s over one hundred and sixty scientific
works had been published in this area? The numbers of scientific works devoted
to this micro-organism has grown tremendously since the 1970s and it is
2
interesting to note that over three hundred enzymes have been purified from
bakers' yeast and doubtless many more exist.8 It has also been shown that many of
these isolated enzymes show activity under very similar conditions: neutral to
mildly acidic aqueous media. This may seem a good thing in that bakers' yeast
shows a wide range of chemical capabilities under these mild conditions. However
this Jversatility' has the price of making bakers' yeast reactions potentially non
selective in the mode of action on the substrate used. This is, in fact, a common
argument among chemists who prefer the selectivity of often expensive isolated
enzymes and brand bakers' yeast reactions as 'intrinsically messy'.9 This is of
course true to varying degrees but their argument against the use of bakers' yeast
is strengthened when one considers that the products from such reactions are
often difficult to isolate from the fermentation broth and are sometimes
contaminated with the cell mass, nutrients, metabolites and unreacted substrate.
A great deal of effort has been focused on these inherent problems and a greater
understanding of the mode of action of the micro-organism has been established. 10
New and novel abilities of the micro-organism are continually being reported in
the scientific press as new substrates are subjected to the various reactions.ll,12 As
more effort is focused on the use of bakers' yeast, the greater the understanding of
the enzymatic processes involved becomes.
It has been the experience of many synthetic chemists that in addition to the
desired transformation, the substrate also undergoes multi-stage transformations
leading to a mixture of products. This problem of selectivity, i.e. controlling the
various enzymatic processes involved with bakers' yeast has become a major area
for research and discussion. As it is already understood that bakers' yeast displays
most of its activity under very similar conditions, chemists have used structure
modifications as the major tool in controlling selectivity. However other methods
have been reported for controlling the reaction such as the control of pH during
reaction,13 immobilisation of the cellular mass,14 the nature of nutrients used,15,16
3
concentration,17 pre-treatment of the cellular mass,18 use of enzyme inhibitors15
and varying the cellular mass/ substrate ratio. This list is by no means exhaustive
and indeed a constant stream of new methods continue to appear in the scientific
literature. When appropriate extraction methodology is used with relatively
inexpensive starting materials at an early point in the synthesis, then the
convenience of obtaining valuable chiral intermediates of high optical purity will
not be significantly influenced by any lack of efficiency.
In general, knowledge of the requirements of bakers' yeast and its mode of action
is limited. This is because the isolated enzymes have only been compared to the
whole microbial system in a few cases. This continues to be an area of great
interest and doubtless will remain so for some time to come.
The Reactions of Bakers' Yeast
(1) The stereoselective reduction of ~-keto esters
The use of bakers' yeast to transform small molecule f3-keto-esters into chiral
intermediates is certainly one of the most popular microbial transformation used
by synthetic organic chemists. The reaction was first reported back in the early
1930s19 but major discrepancies in enantiomeric excess (e. e) and yield meant that it
was not until recently that the reaction was re-examined20-24. Seebach and co
workers studied the effect of the micro-organism on the simple ~-keto ester, ethyl
acetoacetate (1), in an attempt to produce chiral ethyl 3-hydroxybutanoate (2) as
shown in Scheme 1.23 They found the method easy to perform and observed
enantiomeric excesses of greater than 85% in favour of the (5)-(+) isomer (2).
4
o 0
~OEt (1)
(Scheme 1)
OH 0
~OEt (5)-( + )-(2)
Furthermore, the results were found to be reproducible using different brands of
commercially available bakers' yeast and commercially available sugar (sucrose)
overcoming a problem that earlier chemists had encountered. The product was
later crystallised to optical purity via its 3,5-dinitrobenzoate derivative. Optically
active ethyl 3-hydroxybutanoate (2) was shown to be an extremely useful
intermediate in the synthesis of a number of important natural products as shown
in Figure 1 in which the ethyl3-hydroxybutanoate skeleton is highlighted.
o o
.. I' ..... -' 'CHO
Me", -, o
o o
o I,
Me '-.
'OCOMe o
Carbomycin B 25 (3) (R,R)-Pyrenophorin 26 (4)
(5)-( + )-5ulcatol 27 (5)
(Figure 1)
5
Georg and co-workers have also utilised (S)-(+)-ethyl 3-hydroxybutanoate (2)
derived from bakers' yeast reduction in the synthesis of thienomycin (8)28,29, This
is shown in Scheme 2.
OH
(6)
(Scheme 2)
OH ~ H H
OH H
NO (7) OMe
• • •
(8)
S~NH2
Further work on f)-keto esters by Seebach showed that bakers' yeast reduction of 3-
oxoheptanoate (9) gave 3-hydroxyheptanoate (10) with again high enantiomeric
excess (>90%) as shown in Scheme 3 but in this case the (R) enantiomer was
favoured.23
o o
(9)
Bakers' OEt yeast
(Scheme 3)
6
OH o
OEt
(R)-(10)
A hypothesis put forward for this apparent change in selectivity is that the
microbial system has a number of enzymes operating at the same time and these
enzymes are substrate specific and in some way competing against each other. The
need for a rational of these selectivity effects has become a major area of study.
Sih and co-workers propose that there is a relationship between selectivity and the
size of the groups attached to the carbonyl group.31,32 Sih has shown that the
microbial system of bakers' yeast has competing enzymes that deliver hydrogen
selectively to both faces of the molecule. He has also shown that the rates of
reaction of the competing enzymes, when different, lead to an excess of one
enantiomer over the other and chirality is induced.
It follows therefore that the difference in size of the groups adjoining the carbonyl
group should regulate the rate of reduction from each side and thus
stereoselective reduction is observed. In other words the microbial system of
bakers' yeast consists of a number of oxido-reductases each able to distinguish
large and small groups in an enantiomeric way but operating at different rates.
From this came the proposal that the greatest factor that will influence selectivity
will be structure modifications.
Examples of this approach are shown in Table 1 where both ends of a f)-keto acid
derivative have been manipulated and the stereochemical outcome of the bakers'
yeast reduction deduced. Results from this approach have afforded enhanced
yields and more importantly enhanced enantiomeric excesses.
7
Substrate
(1)
(11)
(13)
(15)
(17)
(19)
(21)
(23)
(25)
o 0
Rl~OR2
Rl
Me
Et
Et
CH2N3
n-Pr
Ph
3-butenyl
3-pentenyl
(CH2hOCH2Ph
Bakers' yeast
OH 0
Rl~OR2
R2 Product ee (%)
Et (2)-(5) 100
Me (12)-(R) 100
n-CsH17 (14)-(5) 40
n-CSH17 (16)-(R) 98
H (1S)-(R) 100
Et (20)-(5) 100
K (22)-(R) 100
K (24)-(R) 100
K (26)-(R) 89
(Table 1)
Ref
33
34
10
35
36
37
33
33
38
Enhancement of enantiomeric excess is observed when potassium carboxylates are
used in place of carboxylic esters.39,40 In the 3 examples (21), (23) and (25) of this
shown in Table 1 the reduction has occurred with excellent enantiomeric excess.
This method of enhancement of optical purity has been used en route to a number
of important natural products, one of which is depicted in Scheme 4.41
A number of other significant improvements to the experimental procedure have
been reported which enhance selectivity and chemical yield. These procedures and
modifications will be discussed in a later section.
8
o o
OK
(27)
Bakers' --.. -.Yeast
HO,
'-1-
OH 0
OMe
t (28) I • Steps
• 0
o
O~ H ; - -::" -
-"
Compactin (29)
(Scheme 4)
There has been much interest in the bakers' yeast reduction of a-substituted (3-keto
esters. Here both enantio- and diastereoselection have to be considered when
predicting the likely stereochemistry of reaction products. The racemic substrate
can interconvert and equilibrate via its enolic form as shown in Scheme 5.
o 0
R3¥OR1
OH 0 /'
R2
R3YOR1
R2
(Scheme 5)
9
From a mechanistic standpoint the reduction is likely to occur via one of two
pathways. The first and less likely of these is by enantioselective "hydrogenation"
of the carbon-carbon double bond of the enolic intermediate, although it is known
that tetrasubstituted double bonds are not normally reduced by bakers' yeast. In
the second and more likely case, one of the two enantiomers of the keto tau to mer
is reduced at a much faster rate than the other and this drives the equilibrium
towards the formation of predominantly one stereoisomer. This is more
pronounced the larger the difference in rates between the formation of one isomer
versus the other three. This process is outlined in Scheme 6.
(Scheme 6)
OH 0
R3¥OR1
R2
tS10W
o 0
R3¥OR1
R2
/SIOW , OH 0
R3¥OR1
R2
A number of representative examples of this type of reduction are shown in Table
2.
10
Substrate Rl
(30) H
(31) H
(32) H
(33) Me
(34) Me
(35) Me
(36) Me
(37) Me
(38) Me
o 0
R'YOR' R2
Me
Et
Me
Me
Me
Me
G-li=H=O-I2
G-li=H=O-I2
n-C4H 9
(39) G-I=CHPh Me
Bakers' yeast
Et
Et
i-Pr
Et
t-Bu
n-CsH17
Et
t-Bu
Et
Me
Yield (%) % ee
25 100
70 90
78 90
75 100
57 100
82 98
84 100
36 100
22 100
7 95
(Table 2)
% de Ref
42
43
44
66 45
92 46
98 45
90 47
88 46
34 47
90 48
By analogy to ~-keto-esters, thio- and dithioesters are also reduced with
outstanding syn selectivity by the micro-organism.49 Indeed compounds (42) and
(43) show enantiomeric excesses for the reaction of greater than 96% with syll
preferences of greater than 88%, as shown in Scheme 7.
11
o 0
AtSMe (40)
(42)
Bakers' yeast
Bakers' yeast
(Scheme 7)
OH 0
MSMe (41)
OH 5
MSMe (43)
The dithioester (43) can subsequently be transformed into the corresponding 3-
hydroxy-ester in high yield and its optical purity is maintained. Similar
selectivities are observed with compound (44) which is reduced with 96%
enantiomeric excess and 100% diastereomeric excess (d.e).49 These figures are
higher than for the corresponding oxygen analogue (46).
0 5 OH 5
s~ Bakers' 6--··J(S----yeast ~
(44) (45)
0 0 OH 0
O~ Bakers' 6--···11o~ yeast
...
(46) (47)
(Scheme 8)
12
The reaction has also been applied with some success to the corresponding cyclic
systems and the reduction of 2-ketocycloalkane carboxylates has been studied in
some depth.20,S1 An example of this is shown in Scheme 9 where the
cyclopentanone derivative (48) is transformed to the corresponding alcohol (49) in
62% chemical yield, with 100% diastereomeric excess and greater than 96%
enantiomeric excess.
o o
Bakers I Yeast -----... HO". . ... )L. O-n-C8H17 o
(48) (49)
(Scheme 9)
In the case of cyclohexanone derivatives, it has been found that substitution at the
4-position of 2-oxocyclohexanecarboxylates results in enhanced optical purity in
the reduced product.20,so This is shown in Scheme 10 where the substituted
cyc1ohexanone derivative (50) is reduced in 74% yield with an excellent 98% e.e.
13
o o
OEt
(50)
Bakers' ... Yeast
(Scheme 10)
(51)
The reaction has been extended even further to accommodate heterocyclic
systems. In the case of the sulphur containing heterocycles shown in Scheme 11
the cis-isomers were obtained in all three cases. The f3-hydroxy-ester (53) was
obtained with 85% optical purity 52 and the ~-hydroxy-ester (57) in 95% optical
purity53.
0 0 OH 0
OMe .. C»··loMe s
(52) (53)
0 0
°tfoMe HQ ~OMe ~ " '" " .. Q s
(54) (55)
o
~oMe o
(56) (57)
(Scheme 11)
14
The reduction of oxygen heterocycles is also possible using the micro-organism.
For example the highly substituted six membered oxygen heterocycle (58) is
reduced by bakers' yeast with the reduced product (59) being obtained with
modest diastereoselection (43% e.e.) via kinetic resolution as shown in Scheme
12.54
a a aH a - l
aEt Bakers' D··'" OEt .. Eta
yeast Eta a
(58) (59)
(Scheme 12)
The piperidine derivative (60) was reduced to the corresponding cis-isomer (61) by
Seebach and co-workers in a reported yield of 73% with an enantiomeric excess of
greater than 95% but using a large excess of yeast and no added sucrose.55
Bakers' yeast
(60) (61)
(Scheme 13)
15
2) Stereoselective reduction of a-keto esters and a-keto acids
a-keto esters are readily reduced by bakers' yeast; however, enantiomerically pure
compounds are not always produced. a-Hydroxy ester (63) was obtained in 92%
enantiomeric excess when (62) was fermented with bakers' yeast and the aryl
acetic ester (64) was reduced with almost complete enantioselectivity. The higher
homolog (66), was however, reduced to give the corresponding alcohol (67) in
racemic form demonstrating the unreliability of bakers' yeast on this type of
substrate.20 These results are outlined in Scheme 14.
C02Me Bakers' C02Me Me02C yeast
... Me02C
° ° : : --
° OH (62) (63)
° Bakers' OH
Ph)lco2Me
-... :
yeast Ph~C02Me
(64) (65)
° OH Bakers'
Ph0 Ph~ ... C02Me yeast C02Me
(66) (67)
(Scheme 14)
A study was carried out on a number of linear a-keto esters in the hope of
producing a relationship between chain length and optical purity of products.56
16
The chain length was varied between 3 and 7 as shown in Table 3 and the
substrate was incubated in normal bakers' yeast, immobilised bakers' yeast in
water and immobilised bakers' yeast in hexane. The resulting enantiomeric
excesses varied between 30 and 94%, with a trend of decreasing optical purity of
products with increasing chain length being observed as depicted in Figure 3.
o
(CH~(CH2>n )lC02Et
Substrate n
a 0
b 1
c 2
d 3
e 4
BY =Bakers' Yeast
OH
(ee: Chemical Yield: Configuration)
91:47:5 87:43:5
75:42:5 66:42:5
31:36:5 39:36:5
50:29:5 78:20:5
30:23:5 63:31:5
IMBY=Immobilised Bakers' Yeast
(Table 3)
17
IMBYin Hexane
94:33:5
36:28:5
32:27:5
47:41:R
54:36:R
The effect of increasing chain length on the Bakers' yeast reduction of a-keto
esters.
100 • BY IWater
• IMBY IWater
90 • IMBY IHexane
80
70
60
e.e (%) 50
40
30
20
10
o o 1 2 3 4
Chain Length n
(Figure 2)
18
a-Keto-acids have been successfully reduced uSIng bakers' yeast to furnish
optically active a-hydroxy-acids. In 1910, Neuberg obtained mandelic acid (74) in
optically active form using this approach.57
o OH
(R)-Mandelic Acid
(73) (74)
(Scheme 15)
The insect pheromone (R)-5-hexadecanolide (76) has been prepared by Utaka and
co-workers in enantiomerically pure form using bakers' yeast.58 This is outlined
briefly in Scheme 16.
o o
~ Bakers'
C02H yeast ~ 10
(75) (76)
(Scheme 16)
19
(3) Stereoselective reduction of 1,2- and 1,3-diketones
1,2-Diketones have been converted into the corresponding diols using bakers'
yeast. The diols are often obtained in good yield and with good to excellent e.e's.
The a-diketone (77) was smoothly converted to the diol (79) in a chemical yield of
82% and 97% enantiomeric excess, as shown in Scheme 17.
o 5:) A0
o
(77)
Bakers' ... yeast
(78)
(Scheme 17)
OH s~ ~~s)
OH
t (79) , OH
Hy~OH
(80)
The resulting diol (79) was subsequently converted to L-digitoxose (80) which is a
sugar component of digitalis.59
The reduction of 1,3-diketones (particularly 2,2-disubstituted cyclopentane-1,3-
diones) has been extensively studied. The reactions usually furnish products with
a high degree of optical purity. Brooks used this approach in the reduction of
cyclopentane dione (81) to give the opticaly active synthon (82) in the synthesis of
the natural product corio lin (83) ,as shown in Scheme 18.60,61
20
o
(81)
Bakers' 0 yeast'"
OH
(82) (83)
(Scheme 18)
In general, reductions of 2,2-disubstituted-cyclohexane-1,3-diones with bakers'
yeast give (S)-hydroxyketones.62 Mori and co-workers have reduced 2,2-
dimethylcyclohexane-1,3-dione (84) in this manner to produce (S)-3-hydroxy-2,2-
dimethylcyclohexanone (85) in 79% yield and with >99% optical purity. This was
used as an intermediate in the total synthesis of karahana lactone (86), polygodial
(87) and (+)-dihydroactinidiolide (88) as outlined in Scheme 19.63-66
0 0
(84)
~O (86)
Bakers' 0
yeast .-
/ //
/ / /
CHO
CHO
(87)
(Scheme 19)
21
(85)
t t
0
(88)
(4) Stereoselective reduction of 4 & 5-oxoalkanoic acids and esters
Much interest has been shown in the use of bakers' yeast in the preparation of
naturally occurring y and () lactones67• The reduction of 4- and 5-oxoalkanoic acids
and esters have been achieved with variable success and a variety of lactones have
been prepared by this method with reported enantiomeric excesses usually
exceeding 95%. An example is shown in Figure 4.
Bakers' yeast
(89)
(Figure 3)
o O~,.\\R
(90)
(5) Stereoselective reduction of carbon-carbon double bonds
Enantioselective microbial reduction of a,~-unsaturated aldehydes is well
established. Bakers' yeast has been used for the stereoselective reduction of
I activated' double bonds which have in the main been trisubstituted.68-71 Work in
this field started when Fischer, in 1940, applied the bakers' yeast reduction to a
number of a,~-unsaturated alcohols and aldehydes.72 His work ranged from the
simple crotyl and cinnamyl derivatives through to citral, geraniol and
triglicaldehyde derivatives. His results were only based on optical rotation va1ues,
with relative configurations being assigned where possible. This has led scientists
22
to rediscover his work and particular attention has been paid to the preparative
value of this type of intermediate in asymmetric synthesis. 73,74
Particular interest has been shown in intermediates with a methyl substituent
present on the fl-carbon atom. Synthons (91) are useful intermediates en route to a
number of important natural products containing the isoprenoid unit. The
isoprenoid unit is found in such natural products as tocopherol, phylloquinones,
phytol and insect pheromones. It is synthetically useful if the X and Y groups are
distinguishable and can therefore be manipulated independantly. Bakers' yeast
gives a qUick and efficient way of producing synthons (91) in crural form.
> x y
Synthon (91)
(Figure 4)
An example of this procedure is a synthesis of the intermediate lactone (99) which
has been used successfully in the synthesis of a number of important natural
products such as Vitamin E and the pheromone of Tiboleum castaneum. ~
Furylacrolein (95) has been incubated with bakers' yeast to produce the
corresponding alcohol (98) as the major product. 68 The chemical yield is reported
as 72% with virtually 100% e.e. The authors also show that the allylic alcohol (96)
is reduced by bakers' yeast to give the same product (98) and it is proposed that
the reaction follows the pathway outlined in Scheme 20. The allylic alcohol (96) is
23
in equilibrium with the aldehyde (97) which is itself slowly reduced by the micro
organism. Once reduced, the saturated aldehyde (97) is quickly further reduced to
the saturated alcohol (98). The resulting saturated alcohol (98) was then smoothly
converted to the corresponding lactone (99) by ozonolysis.
cv Fast
~OH ~
o # CHO "'II1II(
(95) (96)
Slow , ~
Fast
~OH ~ .... o CHO 0
(97) (98)
~ Chemical Methods
~ ~ .-' .'
oJ) (99)
(Scheme 20)
Successful bakers' yeast reduction of trisubstituted olefins has also been observed,
to furnish optically active saturated molecules of synthetic interest. Several dienes
containing alcohol or aldehyde functionality have been chosen for this reaction in
order to obtain larger chiral units. These products often contain a proportion of the
functionality of the target molecule already in place. This has been illustrated in
the synthesis of optically active phytol75 and a number of other saturated
pheromones.
24
Studies of the reduction of carbon-carbon double bonds have shown that the
presence of electron withdrawing groups on the alkene are essential for reduction
to take place. a,~-Unsaturated esters are not considered to be good candidates for
this type of reaction76,77. The use of fluoro-substituted-a,~-unsaturated esters and
alcohols have been well documented78 and indeed the reductions occur with good
chemical yield and between 67 and 87% optical purities.
A number of examples of the reduction of cyclic ole fins have also been reported.
An example of this is the reduction of the cyclohexene (100) with bakers' yeast to
give the corresponding saturated cyclohexane-dione (l01). This procedure has
been carried out on a 10 kg scale with a concentration of 20g/L being possible
without yeast poisoning and has led to an isolated yield of 80% in
enantiomerically pure form. This product (101) was then smoothly converted to
zeaxanthin (102) by chemical methods79.
o
(l00)
Bakers' yeast ...
o
(101)
(Scheme 21)
Chemical M~et-=-h-od-:-r
(6) Carbon-carbon bond forming reactions.
HO
(102)
The formation of carbon-carbon bonds is of fundamental importance to any
synthetic organic chemist. Enzyme-mediated carbon-carbon bond forming
2S
reactions are in the main very limited and indeed the few reactions available are
related to enzymatic systems operating within a narrow substrate range80. Bakers'
yeast mediated carbon-carbon bond forming reactions are so far limited to Michael
addition of a carbon nucleophile, sterol formation and acyloin condensation.
(a) Michael-type addition of a carbon nucleophile.
It has recently been observed that addition of 2,2,2-trifluoroethanol (104) to a
fermenting mixture of bakers' yeast and an a,(3-unsaturated ketone or ester
proceeds with the formation of optically active fluorinated carbinols as well as the
expected alcohol reduction product. This type of reaction is outlined in Scheme 22.
/j(R ~R + HO~ o OH o
(103) (104) (l05a) (105b)
(Scheme 22)
Trifluoromethyl carbinols have been shown to be produced in 26-40% isolated
yield with enantiomeric excesses exceeding 90%. When the transformation is
applied to a,(3-unsaturated esters the corresponding lactones are produced via
enzymatic hydrolysis to the intermediate hydroxy-acid. An example of this
26
procedure is shown in Scheme 23 where ethyl acrylate (106) is smoothly converted
into the lactone (109) in 47% yield and 79% enantiomeric excess.
Bakers' CF3
~OEt + F3C..........,.,OH ~ ~OEt yeast HO
0 0
(106) (107) (108)
! F3C~O
(109)
(Scheme 23)
(b) Sterol Formation
Studies have shown that optically active lanosterol derivatives can be derived
from racemic squalene oxides by the use of bakers' yeast. The process is thought to
involve kinetic resolution of the squalene oxide followed by cyclisation of the
polymeric structure. This transformation has been carried out on gram scales and
natural products such as lanosterol (110a), ganoderic acid (110b) and (-)
loanostatriene (110e) have been prepared by this method (Scheme 24).81-83
Reported yields for the reaction are high, in the region of 60-80%, but using
27
modified yeast. The yeast in question is modified by pretreatment of the cellular
mass with ultrasonic radiation, which has the effect of activating the required
enzymes. Bakers' yeast not activated in this way was found to give poor results in
this type of reaction.
(109a-c)
HO 1 2
a R =CHJ,r R =CH3 1 2 b R =H, R =C02H 1 2 c R =CH=CH21 R =CH3
(110a-c)
(Scheme 24)
(c) The Acyloin Condensation
H. J von Liebig found, in 1913, that during the yeast fermentation of furfural (111),
a second product (113) was produced in addition to the expected reduction
product (112)84. Upon further investigation by Neuberg85 this product was found
to be furylic alcohol formed as the acyloin condensation product.
28
OyH ~OH o + O-Jl o : -
o OH
(111) (112) (113)
(Scheme 25)
This reaction has been exploited by many organic chemists and indeed the process
has found its uses in industry including the large scale preparation of (L)
ephedrine (117).86 Benzaldehyde (114) is used as starting material and is converted
to the desired product as shown in Scheme 26.
0 OH OH
H Bakers' yeast
... +
(114) (115) (116)
+ OH
NHMe
(117)
(Scheme 26)
29
Benzaldehyde (114) is reacted with the formal equivalent of acetaldehyde to
furnish the a-hydroxy-ketone (115) and the erythro-diol (116). Enantioselectivity in
both steps is very high and the diol (116) is produced with 95% enantiomeric
excess as shown. This procedure has also been extended to a number of
monosubstituted benzaldehydes with very little depreciation in selectivity.87 The
bakers' yeast mediated acyloin condensation is by no means limited to the use of
benzaldehydes and its derivatives and a,~-unsaturated aldehydes have been
successfully converted into optically active diols in moderate yield and high
enantiomeric excesses. In the case of cinnamaldehyde (118) and a-methyl
cinnamaldehyde (121) as shown in Scheme 27, the (25, 3R) diols are produced in
25% isolated yield and 85-95% ee.89,90
a OH OH
H Bakers' -~ --~
H yeast H a H OH
(118) (119) (120)
a OH OH
H Bakers' yeast
--~
(121) (122) (123)
(Scheme 27)
It has been shown that the steric bulk of the a-substituent has a part to play in the
reaction in that its presence can hinder the process. Indeed a-ethyl and a-propyl
substituted a,~-unsaturated aldehydes do not undergo bakers' yeast mediated
acyloin condensations.
30
Enhancement of chemical yield and enantioselectivity in Bakers'
yeast mediated reactions.
In the majority of cases reported so far in the scientific literature, bakers' yeast
reductions of carbonyl compounds afford satisfactory results, with high chemical
yield and high stereoselectivity. However, there are many examples that have
afforded unsatisfactory results, low chemical yield and/ or low stereoselectivities.
Usually these results are discarded and moreover they are not reported in the
literature. At the same time, the micro-organism may not afford the compound of
desired configuration for further use as a synthetic intermediate. In such cases, the
reduction can be controlled or reversal of stereochemistry can be performed by a
number of reported methods. In this section a number of key experimental
procedures will be outlined which can be used to control both stereochemistry and
chemical yield.
(a) Addition of a third reagent to the reaction system.15
Unsatisfactory stereoselectivity during bakers' yeast reduction occurs when two or
more dehydrogenases operate simultaneously with a number of enzymes
producing the (R)-alcohol and a number producing the (S)-alcohol, each with a
high degree of stereoselectivity.31 It follows, therefore, that if appropriate enzymes
can be inhibited or activated, this will result in higher stereo selectivities.
Nakurama and co-workers adopted this approach and studied the effect of
various additives on the reduction of methyl 3-oxopentanoate (11) with bakers'
yeast. The addition of a,(3-unsaturated carbonyl and hydroxy compounds was
found to be particularly effective and a number of results are outlined in Table 4.
31
o 0 II II ----~
~OMe
(11)
Additive
o
~
~OH
0=0
None
Yeast
DBY BY
DBY BY
DBY BY
DBY BY
DBY BY
DBY = Dried Bakers' yeast BY = Bakers' Yeast
OH 0
~OMe+ R-(12)
Configuration
R R
R R
R R
R R
R R
(Table 4)
32
OH 0
~OMe 5-(12)
ee (%) Yield (%)
68 51 89 22
61 71 78 50
60 68 89 67
44 67 66 68
12 46 37 38
In the absence of any additive, the reduction of methyl3-oxopentanoate (11) with
dried bakers' yeast proceeds with only 12% enantiomeric excess, indicating that a
number of competing enzymes are operating at the same time producing both the
(R)- and (S)-enantiomers. As can be seen from the results, addition of a,f3-
unsaturated carbonyl and hydroxy compounds enhance the optical purity of the
product in favour of the (R)-enantiomer.
N akurama went on to study the effect of adding different nutrients to the reaction
mixture and found that glucose was particularly good at enhancing both chemical
yield and stereoselectivity. A number of his results of the reduction of methyl 3-
oxopentanoate (11) with bakers' yeast are outlined in Table 5.
o 0 \I \I --~
~OMe
(11)
DBY/g Glucose/ g
2 o
2 1
4 o
4 1
OH 0
~OMe+ R-(12)
Configuration ee (%)
R 7
R 23
R 12
R 31
(Table 5)
33
OH 0
~OMe 5-(12)
Yield (%)
41
43
31
61
The enhancement of chemical yield and stereoselectivity observed when a,~
unsaturated carbonyl and hydroxy compounds is believed to result from Michael
type addition of the (S)-producing enzymes onto the additive. This has the effect
of 'tying' the enzymes up and prevents them from reacting with the substrate. It is
also believed that the (R)-producing enzymes are located in different sites which
renders them unable to encounter these inhibitors. In the case of the addition of
glucose, it is believed that the dehydrogenase levels are altered in the yeast and
therefore a change in stereo selectivity can be expected.
(b) Immobilisation of the Cellular Mass14,92.
It has been shown recently by Ohno and co-workers that the configuration and
optical purity of products obtained from bakers' yeast reduction can be
dramatically changed by entrapment of the cellular mass in dense polyurethane
matrices.14,93 It is also reported that such entrapment improves the rather
troublesome isolation procedure from the fermentation broth as the immobilised
cells are easily removed from the reaction mixture by rapid filtration. Ohno found
that in the bakers' yeast reduction of ~-keto esters (123) and (11), enantiomeric
excesses were enhanced substantially by the use of this entrapment procedure. His
results are shown in Tables 6 and 7.
o 0 OH 0 CI II II ---!.~ CI I II + ~OMe ~OMe
(123) 5-(124)
34
OH 0
Cl~OMe R-(124)
Concentration (giL)
10
20
20
a a
Method of Immobilisation
Polyurethane
~OMe (11)
Concentration Method of (giL) Immobilisation
20
20 Polyurethane
Configuration
R-(124)
R-(124)
5-(124)
(Table 6)
OH a
~OMe+
R-(12)
Product
R-(12)
R-(12)
(Table 7)
ee (%)
31
12
90
OH a
~OMe 5-(12)
ee (%)
5
86
Further work by this group has shown similar results when the micro-organism is
immobilised using magnesium alginate and the reaction is run under a high
concentration of magnesium ion.92 Work has been carried out using both ordinary
and immobilised yeast and the effect of various metal salts has been investigated.
Addition of sodium and potassium ions was found to reverse the selectivity of the
reaction and indeed methyl (5)-3-hydroxypentanoate (12) was formed from
methyl 3-oxopentanoate (11) instead of the expected (R)-isomer which is formed
under normal fermentation conditions. As enantiomeric excesses and chemical
35
yields were only found to be moderate using sodium and potassium salts further
studies were conducted. Attention was focused on Group II metal salts and in
particular magnesium and calcium salts. Again reversal of configuration was
observed with greatly enhanced enantioselectivity (75-86% ) but with only
moderate chemical yield. Once the cells were immobilised however the chemical
yield was enhanced to the region of 44-58% making the reaction a viable process
for the synthetic organic chemist. A summary of the results is outlined in Table 8.
o 0 II II -----:~
~OMe
OH 0
~OMe+
Additive (cone)
none
KCI (1.0)
KCI (2.0)
KCI (4.0)
NaCI (2.0)
NaCI (4.0)
MgCh (2.0)
MgC12 (3.0)
CaCl2 (2.0)
(11)
MgCh (2.0) (IMBY)
MgCh (4.0) (IMBY)
Configuration
R
S
S
S
S
S
s
S
S
S
S
R-(12)
e.e (%)
12
8
24
45
43
47
80
86
75
81
89
(Table 8)
36
OH 0
~OMe 5-(12)
Yield (%)
46
54
47
41
37
14
20
1
19
58
44
(c) Substrate Concentration.17
Wipf and co-workers demonstrated that the production of (S)-ethyl 3-
hydroxybutyrate (2) from ethyl acetoacetate (1) was observed with enhanced yield
and optical purity by keeping the concentration of substrate constant during the
reaction. This was achieved by constant addition of a solution of the substrate and
a solution of sucrose to the fermentation vessel. Wipf showed that an optimum
concentration of 0-lg/ L during reaction led to the isolated product having an
optical purity in the range of 95-97%. He also showed that there is a dramatic loss
in optical purity as the concentration of substrate increases above 19/ L. These
results are shown in Table 9 and Figure 6. The course of reaction was also studied
and this is shown in Figure 7.
Substrate Concentration (g/ L) Optical Purity (ee %)
0-1 95-97
5 72
10 70
15 70
20 58
(Table 9)
37
The effect of increasing concentration on optical purity in the bakers' ~east
reduction of ethyl acetoacetate !11
100
90
80
70
60 e.e 50 (%)
40
30
20
10
0 0 5 10 15
Substrate concentration (giL)
(Figure 5)
The course of the reduction of ethyl acetoaceate with bakers' yeast.
100 • • • • 90 ~ • 80 • Optical purity (%)
70 • (s)-Ethyl 3-
20
~ 60
hydroxybutyrate (giL)
" Ethyl acetoacetate 50 (giL)
40
30
20
10
0 0 7 20 29 46 55 70 93 100
Fermentation time (h)
(Figure 6)
38
Chapter Two
Preparation and yeast reduction of the piperidine
derivatives
39
Preparation of the Piperidine Derivatives
During previous work within the group it was shown that racemic keto-proline
(125) could be reduced stereoselectively to the corresponding cis-~
hydroxyproline (126) with excellent optical purity using dried bakers' yeast and
sucrose 94.
Bakers' Yeast
(125) (126)
(Scheme 28)
We decided that it would be interesting and useful from a synthetic standpoint if
the three possible piperidine f3-keto-esters (127), (128) and (129) were subjected to
the bakers' yeast reduction and the subsequent products identified. It is worthy of
note that all three of these piperidine ~keto-esters possess considerable synthetic
potential which make them desirable synthetic targets for organic chemists.
0 50 (yC02R1
CX:OR1 N N '2 ' 2 '2
R R2 R
(127) (128) (129)
(Figure 7)
40
The hydroxy-piperidinecarboxylic acids (130) and (131) have been shown to
influence the functioning of the central y-aminobutyric acid neurotransmitter
system. This is interesting from the point of view of the development of certain
pyschiatric and neurological disorders. 95 4-Hydroxypiperidine-3-carboxylic acid
(130) has been shown to be a potent substrate competitive inhibitor of the
neuronal y-aminobutyric acid uptake process96 and 3-hydroxypiperidine-4-
carboxylic acid (131) has been shown to be a specific y-aminobutyric acid receptor
agonist. 97
(130) (131)
(Figure 8)
From the point of view of both synthetic and pharmacological interest, it is
surprising to find that these compounds have only been available in racemic form
until the present work featuring the use of bakers' yeast on the corresponding (3-
keto-esters provided the compounds in chiral form.
It can be easily envisaged that the piperidine (3-keto ester (128) can be utilised as a
synthetic intermediate en-route to a number of naturally occurring indolizidine
alkaloids including compounds such as swainsonine (132) and castanospermine
(133). To this end the reduction of this intermediate in chiral form may prove
useful in the total synthesis of such compounds, again in chiral form.
41
OB :-. .
IIIIOB
Swainsonine (132)
(128)
Castanospermine (133)
(Scheme 29)
Of the three p-keto-esters we wished to subject to the bakers' yeast reduction, we
were pleased to find that the 3-ethoxycarbonyl-4-oxopiperidine derivative was
commercially available as its hydrochloride salt (134) from the Fluka Chemical
Company. This was subsequently protected at nitrogen as its BOC derivative (135)
by reaction with di-tert-butyl dicarbonate with the use of triethylamine as base.98
Di-tert-butyl dicarbonate / ------~
triethy lamine
(134) (135)
(Scheme 30)
42
The 2-alkoxycarbonyl-3-oxopiperidine (128) was unfortunately not available from
a commercial source and so the search for an expedient synthesis of such a
compound was undertaken in the chemical literature. We were pleased to find
that Rapoport and co-workers had published an article showing the preparation
of the desired compound by a rhodium(ll) acetate dimer-catalysed carbenoid
insertion / cyclisation reaction.99 Work was immediatley undertaken on the
synthesis of this compound which started with the protection of 4-aminobutyric
acid (136) as its benzyloxycarbonyl derivative. Schotten-Baumann conditions of
simultaneous addition of benzyl chloroformate and aqueous sodium hydroxide
were utilised to furnish the desired protected amino acid (137»)00 This was
subsequently activated using N,N' -carbonyldiimidazole and reacted with the
dianion formed by the action of isopropylmagnesium bromide on hydrogen
methyl malonatelOl-103 to produce the corresponding (3-keto-ester (138).
Benzyl chloroformate / -------;~
Sodium hydroxide
(136)
(Scheme 31)
43
HN~C02H I
Z
(137)
l)CDI o·M~
2) t l MeO~o
3) MeOH
H~~C02Me Z 0
(138)
In practise this reaction was found to be cumbersome and poor yielding. We
found that the multi-stage reaction involved here was not tolerant of minor
variations in the experimental procedure and this led to rather variable results. In
order that the desired l3-keto-ester (138) be produced by a more viable pathway
we turned our attention to the use of 2,2-dimethyl-1,3-dioxane-4,6-dione
(Meldrum's acid).104 Again the Z-protected 4-aminobutyric acid (136) was
activated using N,N' -carbonyldiimidazole and the intermediate was reacted with
Meldrum's acid in the presence of pyridine as base.1OS Subsequent breakdown of
the intermediate complex using refluxing methanol led to the desired compound
(138) in 80% isolated yield and high purity, making Meldrum's acid the reagent of
choice for this particular step.
HN~C02H I
Z
(137)
_1.:-) C_D_I __ ~
o~o 2) 0 0 / pyridine
X. 3) MeOH
(Scheme 32)
(138)
Next came the introduction of the diazo functionality between the two carbonyl
groups. This was cleanly achieved using a mixture of p-carboxybenzenesulphonyl
azidelO6 and triethylamine as base. The final cyclisation step to produce the
desired piperidine f3-keto-ester was achieved by the rhodium(II) acetate dimer
catalysed carbenoid insertion into the N-H bond to furnish the desired piperidine
l3-keto-ester (140) after silica gel chromatography
44
(Scheme 33)
HN I
Z o
(139)
(140)
This final reaction proved particularly stubborn in that the course of reaction was
greatly influenced by the time taken for the reaction mixture to reach reflux and
also by minor contaminants in the reagents or substrate. At best a mixture of
compounds was isolated which resulted from the competing reactions of N-Hand
C-H insertion and a reaction of unknown mechanism. These results were also
experienced by Rapoport and co-workers.99
It soon became apparent that a completely new synthetic strategy would need to
be adopted for the synthesis of this piperidine and to this end a Dieckmann
cyc1isation approach was considered. 107 2-Pyrrolidinone (143) was reacted with a
finely divided suspension of molten sodium in refluxing toluene to produce the
corresponding sodium salt which was then quenched with ethyl bromoacetate to
produce the alkylated derivative (144) in 83% yield. Subjection of this product to
the rather harsh conditions of refluxing 6M hydrochloric acid over a period of 2
days furnished the hydrolysed product (145) which was immediatley re-esterified
in acidic methanol to give the diester (146) as a thick gum in an overall yield of
66% for both steps. Without purification, this gum was protected at nitrogen as its
45
BOC derivative (147) using di-tert-butyl dicarbonate and triethylamine and we
were pleased to isolate the protected diester (147) as a thick oil in 85% yield.
c:;'Ao I
H
(143)
1) Sodium (1) ~
2) Ethyl bromoacetate
(147)
(Scheme 34)
6MHCl
Reflux/48hrs CC02H
NH.HCI
lC02H
(145)
MeOH/ Hj)+
(146)
Dieckmann ring closure of this compound using the so called 'non equilibrating'
conditions of potassium tert-butoxide in dry toluene108 furnished the desired
piperidine ~-keto-ester (148) in moderate yield. It was found that this product,
which was the kinetic product from the reaction, rapidly isomerised under the
reaction conditions to produce the thermodynamic product (149). This showed
that the 'non-equilibrating' reaction conditions were in fact allowing equilibration
to occur and indeed the thermodynamic product became the major product from
the reaction. Much work was carried out on this reaction and we were satisfied to
obtain a 2:1 mixture of the two products in favour of the thermodynamic product
(149) by using low temperature and fast reaction times. With appropriate
46
purification techniques this became a viable route to the desired 2-
methoxycarbonyl-3-oxo-piperidine protected as its BOC derivative (148).
(147)
(Scheme 35)
&~ N I
BOC
(149)
The third and final (3-keto-ester (129) has been prepared using the thermodynamic
conditions for Dieckmann ring closure and reduced using bakers' yeast.The
resulting (3-hydroxy-ester has been used as an intermediate en-route to the
naturally occurring compound 3-quinuclidinol (151). This chemistry will be
outlined in a later section (p 82).
OH
CQ} >
3-Quinuclidinol (151) (129)
(Scheme 36)
47
Yeast reduction of the piperidine fi-keto-ester derivatives
The piperidine ~keto-ester (135) was added to a fermenting solution of bakers'
yeast and sucrose in tap water at 35°C.l09 Tap water was required as it was found
that the reduction did not go to completion if deionised or distilled water was
used. Fermentation continued for a period of 24 hours at which time the cellular
mass was removed by filtration through kieselguhr. Extraction of the filtrate with
dichloromethane and subsequent work up of the organic phases led to the
isolation of the desired f3-hydroxy-ester (152) in 74% yield as an off white solid
(m.p 58-60°C). This looked extremely pure by both IH and 13C NMR and
appeared to be a single diastereomer which was fortunate in that any attempts to
purify the compound by silica gel chromatography led to its complete
degradation.111 Futhermore we were pleased to find that the product was chiral
and showed an optical rotation of +25.6°. However, in order that this compound
can be used as an intermediate in any stereos elective synthesis the relative and
absolute stereochemistries of the two newly created chiral centres must firstly be
deduced.
Bakers' yeast/ sucrose / ------~ water 35°C/24h
(135)
(Scheme 37)
48
OH
Q"C02E! N I
BOC
(152)
In order to determine relative chemistry of the hydroxyl and carboxylate
functions, we decided to analyse the coupling of the protons geminal to these
groups. Coupling is mediated by the interaction of orbitals within the bonding
framework and is therefore dependant upon overlap and hence upon the dihedral
angle.
The relationship between dihedral angle and the vicinal coupling constant 3J is
given theoretically by the Karplus equations.
3Jab = JO cos2q> - 0.28 (0° <= cP => 90°)
3Jab = J180 cos2<p - 0.28 (90° <= cp => 180°)
where JO and JIS0 are constants which depend upon the constituents on the carbon
atoms and cp is the dihedral angle.
From this relationship it can be calculated that the coupling constant is largest
when the dihedral angle is 180° (hydrogens in an anti-periplanar arrangement),
slightly lower when the dihedral angle is 0° (hydrogens in a syncoplanar
arrangement) and smallest when the dihedral angle is 90° (hydrogens in an
orthogonal arrangement).
In rigid cyclohexanes the axial axial coupling is usually large, in the range 9-13
Hz, because the dihedral angle is close to 180°. The axial-equatorial and
equatorial-equatorial coupling constants are much smaller, in the range 2-5 Hz
because the dihedral angles are close to 60°. For our purposes the results found for
cyclohexane systems should bear close resemblance to the piperidine systems.
49
Turning our attention to similar compounds in the literature we found that trans
geometry of the protons between the newly created stereo-centres led to a
coupling constant in the order of 10Hz and cis geometry of 2.5Hz (Figure 9).
Trans-&eometry
C02H
Q,."OH '-N~ 13,4
~.HCl H
OH
hA 10.05 Hz (154)
hAS.25 Hz (156)
(Figure 9)
Cis-~eometry
hA2.5 Hz (155)
13,4
To determine the relative stereochemistry of the yeast reduction product we
analysed the coupling constants between the protons on the 3 and 4 positions (b,4)
of the yeast reduction product (152). The proton at the 3-position showed 3
couplings (ddd) one large (J 10.4) and two small (J 4.4 and 2.6). If we consider the
conformations for both diastereomers as shown in Figure 10, we can deduce that
conformation (D) is present i.e. with only one large trans diaxial coupling and 2
smaller axial-equatorial couplings being observed. Thus the data is consistent with
a cis orientation of the ester and hydroxyl functions.
50
Trans-&eometry
Conformation (A) No large trans diaxial coupling
H
V H
Conformation (B) Two large trans diaxial couplings
Cis-geometry
H~e Conformation (C) No large trans diaxial coupling
H
COnfO~ (D) One large trans diaxial coupling
(Figure 10)
In order to determine the absolute stereochemistry of the yeast reduction product
(152), it was necessary to convert this compound into one of known
stereochemistry and subsequently compare optical rotations. To this end we chose
to use the yeast reduction product (152) to synthesise the bis-tosylate (158) which
had a literature [a]D of +54°115 and (R) geometry as shown in Figure 11.
We envisaged that such a synthesis would involve deoxygenation at the 4 position
of the yeast reduction product (152) followed by relevant functional group
interconversions.
51
(JOTS N I
Ts I [aID +54° I R-(158)
(Figure 11)
Firstly the yeast reduction product was further reduced to the corresponding diol
(159) using diisobutylaluminium hydride in toluene)16 This procedure produced
the desired compound (159) only in moderate yield with evidence of unreduced
starting material being present. To this end we decided to use the more powerful
reducing agent lithium aluminium hydride and were pleased to isolate the
desired diol (159) in good yield using this reagent. As we wished to deoxygenate
the secondary alcohol at the C-(4) position of the piperidine, it was necessary to
protect the primary alcohol functionality prior to this. This was smoothly
achieved using tert-butylchlorodiphenylsilane117 and triethylamine with a
catalytic amount of 4-dimethylaminopyridine118 and we were pleased to isolate
the desired tert-butyldiphenylsilyl (TBDPS)-derivative (160) in 79% yield.
OH OH OH 0,,'C02Et (i) 0·"" (ii) O'·""arnDPS ... OH ~ ~
N N N I I I BOC BOC BOC
(152) (159) (160)
Reagents: (i), LiAIHt (ii), TBDPSCL Et3N, DMAP
(Scheme 38)
52
In order to deoxygenate the mono-protected diol (160), we adopted the Barton
methodology of radical deoxygenation119,120 as alternative attempts at reductive
deoxygenation within the group had proved unfruitful.121 The secondary alcohol
moiety was converted into the corresponding thionocarbonate using
pentafluorophenyl chlorothionoformate, pyridine and catalytic n-hydroxy
succinimide. This compound (161) was stable to silica gel chromatography and we
were able to isolate the intermediate in high purity. We then treated this
intermediate (161) with tri-n-butyltin hydride and the radical initiator azo-bis-iso
butyronitrile (AlliN) in refluxing benzene for a period of 30 minutes and we were
pleased to isolate the desired deoxygenated product (162) in an overall 53% yield
for the two steps.
OH
(j"'·· ....... OTBPDS
N I BOC
(160)
(i) (ii)
(161)
Reagents: (i), C6FsO(CS)CL pyridine, n-hydroxysuccinimide (ii), Tri-n-butyltin hydride, AlliN, benzene, reflux
(Scheme 39)
O··'·· ....... OTBDPS
N I BOC
(162)
With the basic skeleton of the desired bis-tosylate (158) now in place, we turned
our attention to the necessary functional group conversions that were required to
complete the synthesis. Removal of the nitrogen protecting group was cleanly
accomplished using an excess of trifluoroacetic acid, which upon basification
53
liberated the free anune (163).123 It was decided to reprotect this amIne
functionality as the tosylate instead of removing the oxygen protecting group at
this stage. We feared that the resulting amino alcohol might have proven difficult
to isolate. The tosylation was achieved using standard tosylation methodology of
tosyl chloride and pyridine 124,125 although a catalytic amount of 4-
dimethylaminopyridinel18 was required to drive the reaction through to
completion. We were pleased to isolate the desired tosylated derivative (164) in
74% overall yield for the two steps.
O"""arnPDS (i) O"""arnPDS ..-N N I I BOC H
(162) (163)
Reagents: (i), Trifluoroacetic acid then NaHC03 (ii), Tosyl chloride, pyridine, DMAP
(Scheme 40)
(ii) O"""arnops ..-N I
Ts
(164)
Turning our attention finally to the oxygen portion of the molecule, we smoothly
deprotected the sHy I moiety using the standard conditions of tetra-n
buty lammonium fluoride in tetrahydrofuran.126 This liberated the free alcohol
(165) which was subsequently tosylated using the conditions outlined for the
nitrogen portion1l8,124,125 and we were very pleased to isolate the desired target
54
bis-tosylate (158) as a white crystalline solid with a melting point of 88-89°C [lit 87-
89°C for the (R)-enantiomerl15].
0·'" 0··'" .' OTBPDS (i) . OH ,... N N I I
Ts Ts
(164) (165)
Reagents: (i), Tetra-n-butylammonium fluoride (ii), Tosyl chloride, pyridine, DMAP
(Scheme 41)
0··'" (ii) . OTs ,... N I
Ts
(158)
We were now left to measure the optical rotation ([a]o) of this compound and
compare it to the literature valuel15 for the (R)-bis-tosylate (158) of +54°. We were
subsequently very satisfied to find that the bis-tosylate (158) derived from our
bakers' yeast reduction product (152) showed an optical rotation of -50.2° under
identical conditions to the literature thus indicating (5)-configuration.
Furthermore this figure allowed us to calculate an enantiomeric excess for the (5)
bis tosylate (158) derived from the bakers' yeast reduction product (152) of 93%.
As we were careful not to enrich the optical purity of the compound during the
synthesis by making relevant checks on column fractions etc., we can also suggest
that the bakers' yeast reduction product (152) has an enantiomeric excess of 93%.
As we had already deduced the relative stereochemistry as being cis and we now
know that the absolute stereochemistry at the 3 position of the yeast reduction
product (152) is (R), we can deduce the absolute stereochemistry at the 4 position
will be (5) as shown in Figure 12.
55
OH
cJS) . ,."C02Et
(R)
N I
BOC
(152)
(Figwe 12)
As a more accurate check of the optical purity of the yeast reduction product (152)
we decided to undertake chiral shift NMR experiments on both the racemic and
chiral bis-tosylates (158). The racemic product (±)-(158) was synthesised by
subjecting 3-piperidinemethanol (166) to the tosylating conditions of tosyl
chloride and pyridine catalysed by 4-dimethylaminopyridine.118,124,125 We again
isolated the desired compound (±)-(158) as a white crystalline solid.
(j0H I
H
(166)
Tosyl chloride, pyridine, DMAP •
(Scheme 42)
I Ts
(±)-(158)
A measured amount of the racemic material was dissolved in deuterochloroform
and to this solution were added small quantities of the europium shift reagent
tris-[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]-europium (ill).
After a number of attempts we were excited to see splitting of a signal
corresponding to one of the aromatic ring protons in the IH NMR spectrum.
Addition of the shift reagent was continued and the splitting eventually gave 2
56
distinct signals although complete base line separation could not be achieved.
When the chiral material was subjected to the same experiments we saw only one
of the two signals in the 1 H NMR spectrum which indicated the complete absence
of one of the enantiomers of the bis-tosylate (158). This indicated that the observed
optical purity of 93% from optical rotation values should be taken as a minimum
value for the reaction.
Conclusion
In conclusion we can say that the bakers' yeast reduction of 1-tert-butyl-3-ethyI4-
oxopiperidine-1,3-dicarboxylate (135) gIves (3R, 4S)-1-tert-butyl-3-ethyl 4-
hydroxypiperidine-1,3-dicarboxylate (152) in 74% chemical yield and with an
enantiomeric excess greater than 93% as shown in Figure 13.
(135)
Bakers' yeast/ sucrose / ~
(Figure 13)
57
OH
0:(5) .,., C02Et
(R)
N I BOC
(152)
[a]D23 +25.6
Yield 73%
e.e >93%
I-tert-Butyl-2-methyl 3-oxopiperidine-l,2-dicarboxylate (148) was also subjected
to the bakers' yeast reduction methodology.109 The piperidine f3-keto-ester (148)
was added to a fermenting solution of bakers' yeast and sucrose in tap water and
fermentation was continued for a period of 24hrs. Removal of the cellular mass by
filtration through kieselguhr followed by extraction into dichlomethane and the
usual work up furnished the desired piperidine-f3-hydroxy ester (167) as a pale oil
in 80% isolated yield. As in the previous example we were pleased to find the
crude product looked extremely pure by 1 H NMR and also appeared to be a
single diastereomer by 13C NMR. All rotameric line splittings were eliminated
when the sample was heated to 333K.ll0 We were also happy to observe that
chirality had been induced in the product as it displayed an optical rotation of
+47.9°. No attempts were made to purify this compound by silica gel
chromatography as we feared this would result in its degradation as in the
previous example.111
(148)
Bakers' yeast/ sucrose / ... water 35°C/24h
(Scheme 43)
58
(167)
In order to determine the relative stereochemistry of the product we again looked
at the coupling constant between the protons of the newly created chiral centres
(J2,3)· However, we believed this case would be a little more complicated than the
last in that we had predicted that the ester functionality would adopt an axial
configuration in the product to avoid steric interactions with the nitrogen
protecting group, a phenomenon often observed with these systems.127 We were
unable to predict whether this would have any influence on the stereochemical
outcome of the bakers' yeast reduction at this stage.
Again an attempt was made to analyse the coupling constants of the newly
created stereo-centres the yeast reduction product (167) and its corresponding
acetatellO. We were unable to measure coupling constants for the C(2)-H or C(3)
H of the yeast reduction product (167) or the C(2)-H and C(3)-H signals of the
corresponding acetate110 as the signals were obscured in the IH NMR spectrum.
No attempts at reducing rotameric line broadening resolved this problem. In
order to confirm relative stereochemistry we hoped that one of the derivatives of
the yeast reduction product would display a clear signal for one of these protons.
If not we predicted double irradiation or NOE experiments would have to be
performed.
In order to determine absolute stereochemistry we again turned to the scientific
literature in the hope that a suitable compound could be found that the yeast
reduction product (167) could be elaborated to. To our delight we came across the
corresponding bis-tosylate of 2-piperidine methanol (169) which had been
synthesised in chiral form with the (R)-form showing an optical rotation of
+56.60
• 128 This meant that the chemistry used in the previous example could be
adapted to the purpose of proving absolute stereochemistry of the second yeast
reduction product in the series (167). We were again required therefore to
deoxygenate the yeast reduction product followed by relevant functional group
59
interconversions to create the desired bis-tosylate (169) and compare its optical
rotation to that of the literature compound.128
O ...... OTs N ." +s I [a]D +56.6° I
R-(169)
(Figure 14)
Lithium aluminium hydride reduction of the yeast reduction product (167)
resulted in its smooth conversion to the corresponding diol (170) in 72% isolated
yield. It was again necessary to protect the primary hydroxyl function prior to the
radical deoxygenation sequence. This was smoothly achieved using tert
butylchlorodiphenylsilane and triethylamine with a catalytic amount of 4-
dimethylaminopyridine117,118 and we were pleased to isolate the desired tert
butyldiphenylsilyl (TBDPS)-derivative (171) in 78% yield after silica gel
chromatography.
O"OH (i) O,·OH (ii) O,·OH N ':"C0
2Me
N '-,." ....... OH '-, ........ OfBDPS ~ ~
N I, I I I
HOC HOC HOC
(167) (170) (171)
Reagents: (i), LiAI~ (ii), TBDPSCI, Et~, DMAP
(Scheme 44)
We were disappointed to find that the Barton deoxygenation procedure adopted
previously using pentafluorophenyl chlorothionoformatel22 proved unsuccessful
on this molecule. We were unable to offer an adequate explanation of this anomaly
60
but decided to modify the radical deoxygenation procedure by uSing N,N'
thiocarbonyldiimidazole.129 On this occasion was were relieved to isolate the
desired thionourethane intermediate (172) after silica gel chromatography. This
compound was to prove even more valuable than we first thought as we were able
to unambigously measure the coupling constant (J2,3) of the C(3)-H which had
been pulled down to l>S.53. and appeared as a double double doublet in the lH
NMR spectrum. The three couplings consisted of one large a 10.4) and two small (J
4.4 and 2.6). If we consider the conformations for both diastereomers as shown in
Figure 15, we can deduce that conformation (C) is present i.e. with only one large
trans diaxial coupling and 2 smaller axial-equatorial couplings being observed.
Thus the data is consistent with a cis orientation of the ester and hydroxyl
functions in the yeast reduction product (167).
Trans-&eomeby
Conformation (A) No large trans diaxial coupling
Conformation (B) Two large trans diaxial couplings
Cis-&eometry
H ~H~
Conformation (C) One large trans diaxial coupling
O(CS)Im
Conformation (D) No large trans diaxial coupling
(Figure 15)
61
Focusing on the deoxygenation of the thiourethane derivative (172), the use of tri
n-butyltin hydride in refluxing benzene furnished the desired deoxygenated
derivative (173) in 53% yield after column chromatography.
O··,OH
:.. arnDPS N "/
(i)
I BOC
(171) (172)
Reagents: (i), Im2CS, pyridine (ii), Tri-n-butyltin hydride, AlliN, benzene
(Scheme 45)
(ii) 0 .. N .... ', /OTBDPS I
BOC
(173)
Removal of the nitrogen protecting group was again cleanly accomplished using
excess trifluoroacetic acid which upon basification liberated the free amine
(174)123. Tosylation was achieved using tosylation methodology of tosyl chloride
and 4-dimethylamino-pyridinel18,124,125. We were pleased to isolate the desired
tosylated derivative (175) in a yield of 70% after silica gel chromatography.
(i) (li) • 0 .. , ...... OTBDPS
~ 0 .. , ...... OfBDPS 0 .......... OTBDPS N 'I N 'I N 'I
1 I I BOC H Ts
(173) (174) (175)
Reagents: (i), Trifluoroacetic acid (li), Tosyl chloride, pyridine, DMAP
(Scheme 46)
62
Turning our attention finally to the oxygen portion of the molecule we smoothly
deprotected the silyl moiety using the standard conditions of tetra-n
butylammonium fluoride in terahydrofuran.126 This liberated the free alcohol
(176) which was subsequently tosylated using the conditions outlined for the
nitrogen portion and we were pleased to isolate the desired target bis-tosylate
(169) as a viscous colourless oil in 75% yield.
(i) 0 .. , ..... OTBDPS • 0 .. OH N " N "1'1/ , , Ts Ts
(175) (176)
Reagents: (i), Tetra-n-butylammonium fluoride (ii), Tosyl chloride, pyridine, DMAP
(Scheme 47)
(ii) .. 0 .. , ..... Ofs N " , Ts
R-(169)
We were left now to measure the optical rotation ([a]D) of this compound and
compare it to the literature value for the (R)-bis-tosylate (169) of +56.6°.128 We
were subsequently very satisfied to find that the bis-tosylate (169) derived from
our bakers' yeast reduction product (167) showed an optical rotation of +55.0°
thus indicating (R)-geometry also. Furthermore this figure allowed us to calculate
an enantiomeric excess for the bis-tosylate derived from the bakers' yeast
reduction product (167) of 97%. As we were careful not to enrich the optical
purity of the compound during the synthesis by making relevant checks on
column fractions etc we can also state that the bakers' yeast reduction product
(167) also has an enantiomeric excess of 97%. As we had already deduced the
relative stereochemistry as being cis and we now know the absolute
stereochemistry at the 2 position of the yeast reduction product (167) is (R), we
63
can deduce the absolute stereochemistry at the 3 position will be (5) as shown in
Figure 16.
(167)
(Figure 16)
As a more accurate check of the optical purity of the yeast reduction product, we
again decided to undertake chiral shift NMR experiments on both the racemic and
chiral bis-tosylates (169). The racemic product (±)-(169) was synthesised by
subjecting 2-piperidinemethanol (177) with the tosylating conditions of tosyl
chloride and pyridine catalysed by 4-dimethylaminopyridine. We again isolated
the desired compound (+)-(169) as a thick colourless oil.
(177)
Tosyl chloride, pyridine, DMAP
(Scheme 48)
(±)-(169)
A measured amount of the racemic material was dissolved in deuterochloroform
and to this solution were added small quantities of the europium shift reagent
tris- [3-(heptafluoropropylhydroxymethylene )-( + )-camphorato ]-europium (III).
After a number of additions of the reagent we saw splitting of a signal
64
corresponding to one of the aromatic protons in the 1 H NMR spectrum. Addition
of the shift reagent was continued and the splitting eventually gave 2 distinct
signals although complete base line separation could not be achieved. When the
chiral material was subjected to the same experiments we saw only one of the two
peaks in the 1 H NMR spectrum which indicated the complete absence of one of
the enantiomers of the bis-tosylate (169). This indicated that the observed optical
purity of 97% from optical rotation values again should be taken as a minimum
value for the reaction.
Conclusion
In conclusion we can say that the bakers' yeast reduction of 1-tert-butyl-2-methyl
3-oxopiperidine-1,2-dicarboxylate gtves (2R, 3S)-1-tert-butyl-2-methyl 3-
hydroxypiperidine-1,2-dicarboxylate in 80% chemical yield and with an
enantiomeric excess greater than 97% as shown in Figure 17.
Bakers' yeast/ sucrose / ------~
water 35°C/24h
(148)
(Figure 17)
65
(167)
[a]o23 +47.9
Yield 80%
e.e >97%
Chapter Three
Synthesis of (R)-3-quinuclidinol
66
Introduction to quinuclidines
The quinuclidine nucleus is of synthetic interest to the organic chemist in
connection with the number of naturally occurring alkaloids that contain this unit.
Indeed large families of alkaloids such as the sarpagine, ajamine and cincona
families boast this nucleus as part of their structure. 130, 131, 132, 134
"Quinuclidine"
(Figure 18)
It is interesting to note that the chemistry surrounding quinuclidine is limited
with only a small amount of work being reported in this area. Moreover there
have been hardly any reports of the enantioselective synthesis of quinuclidines
and their associated analogues in the scientific literature to date. Optically active
quinuclidines and their derivatives are extremely important to both chemists and
pharmacologists alike. In particular, 3-quinuclidinol (151) is interesting in the fact
that its associated esters show anticholinergic properties.l35 3-
Acetoxyquinuclidine (178) is one such compound which is one of the few
muscarinic agents that are more active as tertiary amines than as quaternary
ammonium salts.136 In addition to its peripheral effects, 3-acetoxyquinuclidine
(178) also shows central effects upon systemic administration causing tremor,
analgesia and hypothermia in mice)37 Barlow and easy have shown that the
enantiomers of 3-acetoxyquinuclidine (178) display different levels of biological
activity,138 (S)-3-Acetoxyquinuclidine (178) has 10 times the level of activity on
guinea pig ileum than the corresponding (R) enantiomer. Furthermore, the
67
methiodate (179) of (R)-3-acetoxyquinuclidine (178) displays a 40 fold increase in
activity over the corresponding (5) enantiomer.
0
gJ~ CQro CN
Ao R-(178) 5-(178)
0
Q)~ Cw. If
Cw~o If Ao
R-(179) 5-(179)
(Figure 19)
Barlow and easy as well as Weinstein and co-workers have shown that 3-
acetoxyquinuclidine (178) embodies all the functional groups of acetylcholine
(180) in a fairly rigid structure.138,139 Furthermore, it is proposed that the (5)
enantiomer is a particularly good model for discussing fit to the muscarinic
receptor.
5-(178) (180)
(Figure 20)
68
The differing levels of biological activity associated with the enantiomers of 3-
acetoxyquinuclidine (178) is not uncommon in this and indeed many other areas
of work. 3-Quinuclidinyl benzilate (181) also shows a widely different level of
activity in each enantiomer140.
o
01. Ph r1 J"" ~Ph
£N~ OH £&0 1 Ph .... ~Ph OH
R-(181) 5-(181)
(Figure 21)
In general, the enantiomers of 3-quinuclidinol (151) have been separated by
resolution of their corresponding diastereomeric salts. Sternbach and Kaiser were
able to obtain (S)-3-quinuclidinol (151) in optically pure form back in 1952 by
resolution of the racemate with lO-camphorsulphonic acid (182»)41 However the
method was found to be low yielding and moreover the (R)-enantiomer could not
be isolated by this method.
---~
(±)-(151) (182) 5-(151)
R-(151)
(Scheme 49)
69
Kalir and co-workers later prepared (S)-3-quinuclidinol (151) by N-benzylation of
the racemate followed by conversion of the quaternary base into the dibenzoyl-D
tartrate salt. Subsequent resolution of the salt followed by hydrogenolysis yielded
the desired (3)-quinuclidinol (151) in chUal form.142
Dahlbom and co-workers simplified this procedure significantly by resolving
racemic 3-acetoxyquinudidine into its (R) and (5) enantiomers using (+) and (-)
tartaric acid (183).143 The enantiomeric esters were obtained in high yield and
with high optical purities by this method. In order to obtain chiral3-quinuclidinol
by this method it was simply necessary to hydrolyse the chUal esters in alkaline
media.
(+)-(178) (183) 5-(178)
(Scheme SO) R-(178)
As mentioned earlier in the chapter, research into the area of quinuclidines and
their derivatives has been somewhat scarce. This has also been the case for 3-
quinuclidinol with only a handful of syntheses reported for the racemate and even
less for the chiral material. Aaron and co-workers published a synthesis of the
racemic material by cyclodehydration of (4-piperidyl)-1,2-ethanediol (186), in
1965.144 4-Vinylpyridine (184) was oxidised in cold aqueous potassium
permanganate to furnish 4-(pyridyl)-1,2-ethanediol (185) which was subsequently
70
hydrogenated to produce the desired material ready for cyclodehydration (186).
Treatment of this compound with activated alumina at 3000 e for 1 hr led to the
desired racemic 3-quinuclidinol (151).
(184)
(151)
(i) ---~
(iii) 1l1li(
Reagents: (i) KMn04(aq) (ii) H2/ Pt02 (iii) Alumina/ 3000 e
(Scheme 51)
OH
(185)
!<ii) OH
(186)
Interestingly, Fleet and co-workers have published a number of syntheses of
chiral 3-quinuclidinol (151) that will allow introduction of key functionality into
the final cyclised product.145,146 It is a common feature of the alkaloids that
contain 3-quinuclidinol, that the base is substituted with a one carbon chain on
one of the ring bridges and a two carbon chain on one of the other ring bridges.
71
Fleet proposes that such a system could be generated by either of the two
strategies outlined in Scheme 52.
OH
(i)
<
(Scheme 52)
(ii) HO
> OH
OH 6
The first approach (i) involves the introduction of the two carbon chain destined
to become the bridge of the quinuclidine ot C-(4) of the hexose; the two carbon
substituent is therefore introduced at C-(5). The second approach (ii) involves the
introduction of the bridge of the quinuclidine at C-(3) of the hexose and therefore
the two carbon substituent is at C-(2).
In the first approach (i) Fleet synthesised (S)-3-quinuclidinol (151) from (D)
glucose. A two carbon unit is introduced initially at C-(4) of glucose which is
subsequently joined by nitrogen to the C-(6) position of the sugar to form an
intermediate lactam (192) which is further elaborated to form the quinuclidine
framework. Methyl a-D-glucopyranoside is converted to the corresponding diol
(188) by known methods)47 Treatment of the diol with N,N-dimethylacetamide
dimethyl acetal148 gave the amide (189). This was mesylated and the
corresponding mesylate group in the product (190) displaced by azide to furnish
72
the azidoamide (191).
(188)
0jNMe2
~ __ "I'
MeO,,··lo"cCH N 2 3
(iii) <iIIII(
(191) (190)
Reagents: (i) MeC(OMehNMe21 diglyme then K2C0.3 (ii) MeS02Cl/ pyridine (iii) ~a~3/J)~
(Scheme 53)
The resulting azidoamide (191) was hydrogenolysed over palladium black which
resulted in saturation of the double bond and reduction of the azide portion to the
corresponding amine which cyclised in the presence of lithium diisopropylamide
to the intermediate lactam (192) which was further reduced with lithium
aluminium hydride and protected as the benzyl carbamate (193).
73
0jNMe2
ex·' , ,,-
Mea"" 0 CH2N 3
(i) ---~
(191)
Reagents: (i) H2, palladium black, ethanol then LD A (1.1 equiv)
(ii) LiAIH4 then PhCH20COCl/ NaHC03
(Scheme 54)
H
MeO' I"~
(192)
~ (ii)
H
MeO""WZ H
(193)
Reaction of (193) with titanium tetrachloride149-150 in CDCh (to allow monitoring
of reaction by NMR) followed by addition of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) led to the formation of the vinyl ether (194) which was subjected to
ozonolysis and sodium borohydride reduction151 to furnish the diol (195).
H
" .. ~Z MeO lo~~ H
(193)
Reagents:
(i) TiC~ in CDC13 then addDBU
(ii) 0 3 in MeOH/ CH2Cl2
then NaBH4
(i) ---~
(Scheme 55)
74
H
H
(194)
! (iil HO~"D"
NZ HO (195)
Fleet envisaged the final cyclisation to produce (S)-3-quinuclidinol would involve
mesylation and subsequent deprotection at nitrogen to allow cyclisation to take
place. However, release of the amine functionality by hydrogenation of the
mesylate (196) led to spontaeneous ring closure with the formation of the
tetrahydrofuran (197) in which intramolecular attack by oxygen had competed
successfully with the anticipated attack by nitrogen. Fleet also found that the
tetrahydrofuran (197a) could be formed by treatment of the protected piperidine
mesylate (196) with base.
OMs
•. \\OH
(196)
~ (iii)
(197a)
Reagents:
(i)
(i)
(i) H2/ palladium black, ethanol (ii) Ethanol 60° (iii) NaH/THF
(Scheme 56)
OMs
(196a)
~(ii)
(197)
It was therefore necessary to protect the secondary hydroxyl function of the
piperidine mesylate (196) prior to deprotection at nitrogen. This method furnished
75
the desired quinuclidinol (198a) as its silyl ether which was deprotected at oxygen
using trifluoroacetic acid to give the target compound (151) with an optical
rotation of +35.2° (c, 0.23 in IN HCI) [lit +43.8° (c, 3.0 in IN HCI)].152,153
OMs
,."OH (i)
(196)
Reagents: (i) CF3S0piMe2 tBu/ lutidine
OMs
.. "OTBDMS
(198)
I (ii) ,
(198a) R= TBDMj (151) R=OH
(ii) H2/ palladium black then ethanol 60°
(iii) TFA (aq)
(Scheme 57)
(iii)
In the case of Fleet's second approach (ii), the introducton of the 2-carbon bridge
of the quinuclidine was achieved at C-(3) of the hexose. Oxidation of diacetone
glucose (199) with pyridium chlorochromate was followed by treatment with
76
carbomethoxymethylene triphenylphosphorane. Subsequent hydrogenation over
palladium and reduction with lithium aluminium hydride gave the primary
alcohol (200).154 Mesylation followed by displacement of the mesylate
functionality with azide gave 3-(2 -azidoethy 1)-3-deoxy -1,2:5 ,6-di-0-
isopropylidene-allofuranose (201).
0 0
)(0 (i) )(0 .11·0 "110
'. X: ·"O~ " HO
0
(199) HO
~ (iil 0
)(0 .11'0
·"O~
N3 (201)
Reagents: (i) Pyridinium chlorochromate; Ph~CHC02Me; H2/Pd/MeOH; LiAlH4/THF
(ii) MsCl/ pyridine; NaN3/DMF
(Scheme 58)
Mild hydrolysis of (201) gave the diol (202) which was oxidised with period ate
and hydrogenated over palladium black. The resulting amine was protected using
77
benzyl chloroformate to give (203) in which the first of the required rings of the
target molecule had been formed. Methanolysis of this intermediate in the
presence of acid ion exchange resin gave a mixture of a- and ~-furanosides (204).
HO
HO .1. 10 (i) .1. 10
·"O~ ... ·"0 X:
N3 (201) N3 (202)
~ (ii)
tI (iii) ZNW OMe ~ "'0
H ... H ·;ok OH
(204) (203)
Reagents: (i) AcOH/MeOH/H20 (ii) NaI04 /MeOH; H2/palladium black, AcOH;
PhCHPCOCl! NaHC03 (iii) Dowex (H+) resin/MeOH
(Scheme 59)
Deoxygenation usmg Barton methodology 119 followed by hydrolysis of the
78
intermediate (206) gave the lactol which was reduced with sodium borohydride to
give the diol (196).
(i) OMe ----~
(204)
o.0H ZN OH
'~I') (iii)
(196)
Reagents: (i) N aH, CS2, Mel (ii) BU3SnH, AIBN, xylene (iii) CF3C02H; NaB~/ EtOH
(Scheme 60)
(205)
{ (ti)
H
(206)
OMe
OMe
As (196) has already been converted to chiral (S)-3-quinuclidinol (151) this
approach represents another enantioselective synthesis of the molecule.
79
In the case of the third and final piperidine-~-keto ester we wished to subject to
the bakers' yeast reduction methodologyl09 we were pleased to find that it was
initially available commercially as its methyl carbamate from the Aldrich
Chemical Company.
(207)
(Figure 22)
However with work well underway in this area, we were disappOinted to find
that the compound had been discontinued by the company in question and we
were forced to design our own synthesis in order to carry on the project.
Having received considerable success with the preparation of one of the
previous piperidine ~-keto esters (148) via Dieckmann cyclisation,107 we
decided that it would be a good idea to adopt this approach here. We also
recalled the fact that a similarly substituted piperidine-~-keto ester protected as
the tert-butyl carbamate (149) could be formed as the major product from a
Dieckmann cyclisation.
The diacid (145) produced as described earlier was re-esterified, this time using
acidic ethanol in place of methanol to afford the corresponding diethyl ester
(208) in a satisfying 84% yield. This was subsequently protected at nitrogen as
its methyl carbamate using methyl chloroformate and triethylamine and we
were pleased to isolate the desired protected material (209) as a colourless oil in
70% yield.
80
CC02H MeOH/ CCo,EI MeOCOCIL C~2EI
H30+ ~
N.HCI N.HCI Et3N ~
lCo,H l N C02Et I C02Me
C02Et
(145) (208) (209)
(Scheme 61)
We had already learned from previous work on the cyclisation that the kinetic
product from the Dieckmann cyclisation (the 3-oxo, 2-ester moiety) rapidly
isomerised under the reaction conditions of potassium tert-butoxide and dry
toluene at O°C to give the thermodynamic product (namely the 3-oxo, 4-ester
moiety). To this end we decided to adapt the reaction conditions to favour the
thermodynamic product we now desired even more by running the reaction
for longer periods at room temperature to allow even further equilibration.
Potassium tert-butoxide was again used as the base and we were satisfied to
obtain a yield of 51% for the isolated product after column chromatography.
(209)
tsuoKL tolu,tne
25° /lh
(Scheme 62)
(207)
Once a plentiful supply of the reqUired starting material (207) was at hand we
decided to subject it to the bakers' yeast reduction reaction as before.109 The
compound was added to a fermenting solution of bakers' yeast and sucrose in
81
tap water and fermentation continued for 24hrs. After this time the cellular
mass was removed by filtration through kieselguhr and the product extracted
into dichloromethane. Work up of the organic fractions led to the desired
piperidine-(3-hydroxyester (210) in an isolated yield of 89%. Again we were
fortunate in that the product looked extremely pure by 1 H NMR and therefore
did not require purification by silica gel chromatography. Furthermore the
compound appeared to be a single diastereomer by 13(: NMR and as
importantly showed an optical rotation of -21.40•
(207)
Bakers' yeast/ sucrose / ..
(Scheme 63)
(210)
Previous work within the group has shown that the isolated piperidine-(3-
hydroxyester (210) shows a diastereomeric excess of 99.5% and an enantiomeric
excess of 89.4% by chiral column gas chromatography. 133
In order to determine the relative stereochemistry of the yeast reduction
product we again analysed the coupling constants between the protons on the
3 and 4 positions (13,4) of the yeast reduction product (210). The 3-proton was
obscured in the 1H NMR spectrum, however the proton at the 4-position
showed 3 couplings (ddd) one large 0 10.6) and two small 0 4.7 and 2.4). If we
consider the conformations for both diastereomers as shown in Figure 23, we
can deduce that conformation (D) is present i.e. only one large trans diaxial
82
coupling and 2 smaller axial-equatorial couplings being observed. Thus the
data is consistent with a cis orientation of the ester and hydroxy I functions.
Trans-&eometry
Conformation (A) No large trans diaxial coupling
Conformation (B) Two large trans diaxial couplings
Cis-&eometry
Conformation (C) No large trans diaxial coupling
OH
Conformation (D) One large trans diaxial coupling
(Figure 23)
In the previous two cases, we degraded the yeast reduction products (152) and
(167) in order to determine their absolute stereochemistries. In this example
we were excited when we realised that the yeast reduction product (210) could
be elaborated to the natural product 3-quinuclidinol (151). 3-Quinuclidinol
(151) is well documented in the literature and the optical rotation of its
enantiomers are known152,153. Once the compound is synthesised from the
83
piperidine-~-hydroxyester (210) it will be a matter of comparing optical
rotations to determine absolute stereochemistry.
OH
-~-~-~-~ CQ} (210) 3-Quinudidinol (151)
(Scheme 64)
In a retrosynthetic sense we envisaged the penultimate step being the
cydisation of a free amine onto a tosylate or mesylate as shown in Scheme 65.
(151)
>
R=Me (212) R=MeC6H4 (213)
(Scheme 65)
84
OH
It can be easily envisaged that such a precursor will be derived from the bakers'
yeast reduction product (210) by a one carbon homologation at the 4-position
side chain of the piperidine. One problem that we saw from the onset was the
removal of the methyl carbamate group in order to effect cyclisation. We
realised the conditions of iodotrimethylsilane would be too harsh in the
presence of the tosylate / mesylate functionality so we aimed to exchange
protecting groups at a suitable point in the synthesis.
In a forward sense we further reduced the bakers' yeast reduction product (210)
using sodium borohydride in methanol and we were pleased to isolate the
desired diol (214) in 68% yield after column chromatography. The use of
lithium aluminium hydride as in the previous two examples would not be
possible as this would reduce the methyl carbamate to the corresponding N
methyl derivative which would not allow the remainder of the envisaged
synthesis to be carried out.
We envisaged chain extension at the 4-position would be afforded by cyanide
displacement of a suitable leaving group. The piperidine diol (214) was
smoothly converted to the corresponding mono-tosylate (215) in 84% yield
using a mixture of tosyl chloride and triethylamine in dichloromethane)24,125
It is interesting to note that none of the corresponding bis-tosylate was isolated
and indeed the compound refused to form even with the assistance of 4-
dimethylaminopyridine.118 Subsequent cyanide displacement of the tosylate
portion was achieved using sodium cyanide in dimethylsulphoxide at 50°C for
6h. The resulting nitrile was hydrolysed in situ for 16h by the addition of 12M
hydrochloric acid to the reaction mixture. We were pleased to isolate the
desired lactone (216) from the reaction mixture as a colourless oil in 88% yield
85
after column chromatography.
(210) (214)
Reagents: (i) NaBH4/ methanol (ii) Tosyl chloride/Et3N
(ii)
(iii) NaCN/DMSO then 12M HCI
(Scheme 66)
(215)
! (iii) o
(216)
With the lactone (216) in hand we believed that this might be a good point in
the synthesis to effect protecting group exchange at nitrogen. To this end the
lactone was treated with iodotrimethylsilane in chloroform. After heating for
5 hours at 50°C we were pleased to see the disappearance of the methyl
carbamate by IH NMR. The resulting free amine (217) was reprotected this
time as the tert-butyl carbamate and we were pleased to isolate the desired
86
lactone (218) in an overall yield for the two steps of 95% after column
chromatography.
o o o
(i) (ii)
N I
BOC
(216) (217) (218)
Reagents: (i) TMSI then MeOH (ii) Di-tert-butyl dicarbonate/Et3N
(Scheme 67)
We envisaged the remainder of the synthesis would involve reduction of the
lactone (218) to the corresponding diol (219) followed by esterification of the
primary hydroxyl function as the mesylate (221). The final cyclisation would
then be achieved by removal of the nitrogen protecting group in mild acid
followed by heating of the resulting amino mesylate.
Reduction of the lactone (218) proceeded smoothly with sodium borohydride
in ethanoI151 and the corresponding diol (219) was isolated in 68% yield.
Mesylation of the resulting diol however did not furnish the expected product
(221) as there was no methyl signal associated with the mesyl group in the IH
NMR spectrum. Turning our attention to the literature we found that Fleet
and co-workers had also experienced a similar problem145 and they had
87
produced the trans-tetrahydrofuran (198) instead of the desired quinuclidine
skeleton in their synthesis of 3-quinuclidinol (151).
OMs
(i)
(196)
Reagents:
(i) H2/ palladium black, ethanol (ii) Ethanol 60°
(Scheme 68)
OMs
.. "OH
(197)
~ (ii)
(198)
It was felt that our system was even further disadvantaged than Fleet's in that
there was a even stronger possibility that the cis-tetrahydrofuran could be
formed. Preliminary data on the compound indicated this to be the case and
indeed we believe that the hydroxy-mesylate underwent spontaeneous ring
closure under the reaction conditions to produce the aforesaid tetrahydrofuran
(220).
88
o
HO (i) OH (ii) ----~
(218) (219) (220)
MsO
OH
Reagents: (i) N aBH4/ ethanol (ii) Mesyl chloride/Et~
(221)
(Scheme 69)
We felt that one possible solution to the problem would be to protect the
secondary hydroxyl function prior to the cyclisation procedure. We were
disappointed to find that we were unable to achieve any derivatisation of the
secondary alcohol, a phenomenon we experienced earlier when bis-tosylation
of the diol (214) was attempted. At this point in the synthesis we decided to
adopt a new route to 3-quinuclidinol (151) and to this end the original
sequence was abandoned.
By this time we had collected a plentiful supply of the piperidine-~-keto ester
(149) which, as discussed earlier, had been the "unwanted" thermodynamic
product from the Dieckmann cyclisation which produced l-tert-butyl-2-
methyl-3-oxopiperidine-l,2-dicarboxylate (148). It was therefore decided that it
would be advantageous to subject this compound to the bakers' yeast
reduction methodoiogyl09 and use the resulting reduced material as the
precursor to our target compound 3-quinuclidinol (151). The compound was
89
added to a fermenting solution of bakers' yeast and sucrose in tap water and
fermentation continued for 24hrs. After this time the cellular mass was
removed by filtration through kieselguhr and the product extracted into
dichloromethane. Work up of the organic fractions led to the desired
piperidine-~-hydroxyester (222) in an isolated yield of 81%. Again we were
fortunate in that the product looked extremely pure by 1H NMR and therefore
did not require purification by silica gel chromatography. Furthermore the
compound appeared to be a single diastereomer by 13(: NMR and as
importantly showed an optical rotation of -32.7°.
5~ N
Bakers' yeast/ sucrose / -----=---~
water 35°C/24h I BOC
(149) (222)
I [alD23 -32.7 (c=1.0 in CHC~)
(Scheme 70)
In order to determine the relative stereochemistry of the yeast reduction
product we analysed the coupling constants of the 4-proton as in the previous
example as the 3-proton was obscured in the 1H NMR spectrum. Again 3
couplings (ddd) were present for this proton, one large (J 10.6) and two small
(J 3 and 3). If we consider the conformations for both diastereomers as shown
in Figure 23 then we can deduce that conformation (D) is again present i.e.
only one large trans diaxial coupling is present with 2 smaller axial-equatorial
couplings being observed. Thus the data is again consistent with a cis
orientation of the ester and hydroxyl functions.
90
Turning our attention to the synthesis of 3-quinuclidinol (151) in order to
determine absolute stereochemistry of the yeast reduction product (222), we
recalled the problems we encountered previously with the secondary hydroxyl
function attacking the mesylate moiety and effecting spontaneous ring closure
to form the tetrahydrofuran (220). We decided to protect the secondary
hydroxyl function from the onset as the methoxymethyl ether (223). This was
smoothly achieved by treatment with chloromethyl methyl etherl54 and
diisopropylethyl amine (Hunig's base)155 and we were pleased to isolate the
desired protected product (223) in 92% yield after silica gel column
chromatography. Turned our attention now to the chain elongation that was
required at the C-4 position of the piperidine ring, we decided to adopt Arndt
Eistert homologation methodology156-158 which was to involve treatment of
the protected hydroxy acid derivative (224) with oxalyl chloride followed by
diazomethane and silver benzoate in methanol159-160
The required hydroxy acid (224) was produced by hydrolysis of the protected
yeast reduction product (223) in aqueous potassium hydroxide in almost
quantitative yield. Reaction of the carboxylic acid (224) firstly with freshly
distilled oxalyl chloride furnished the acid chloride which was treated in situ
with an excess of an ice cold ethereal solution of diazomethane.
Chromatography of the residue gave the intermediate diazoketone (225) which
showed a characteristic peak for the proton adjacent to the diazoketone group
at 5.31 ppm in the IH NMR spectrum. This intermediate was subsequently
treated with silver benzoate and triethylamine in ethanol to effect the Wolff
rearrangement and we were pleased to isolate the desired homologated ester
(226) as a colourless oil after silica gel chromatography in good yield.
91
5~H C02Me
(i) a OMOM (ii)
~ .. N I N BOC I
BOC
(222) (223)
H
OMOM .. (iv)
(226)
Reagents: (i) MOM-ClI Hunigs base (ii) KOH (aq) (iii) Oxalyl chloride/DMF then diazomethane (iv) Silver benzoate/ Et~ / ethanol
(Scheme 71)
&OMOM
N I
BOC
(224)
N2 t (iii)
OMOM
(225)
Reduction of the ethyl ester functionality to the corresponding alcohol was
achieved by treatment with diisobutylaluminium hydride in toluene at
-78°C161. After work up with potassium tartrate the desired material (227) was
isolated in an adequate 55% yield. To effect cydisation to the required
quinudidine framework we again decided to esterify the hydroxy function as
the corresponding mesy late and release the free amine in the hope that
cydisation would occur. Standard mesylation conditions162 of
methanesuphonyl chloride and pyridine in dichloromethane afforded the
desired mesylate (228) which we were pleased to be able to isolate from the
reaction mixture on this occasion. Removal of the nitrogen protecting group
was subsequently achieved using trifluoroacetic acid123 in dichloromethane
92
and we were delighted that after heating of the residue in ethanol for 6h, the
desired 3-quinuclidinol protected as the hydroxymethyl-methyl ether (229) was
isolated in a moderate 27% yield. Furthermore the compound showed an
optical rotation of -23.40
•
OMOM (i)
(226)
N I
BOC
(227)
OH OMOM
Reagents: (i) DffiAL-H in toluene (ii) Mesyl chloride/ pyridine (iii) TFA then EtOH/ ll.
(Scheme 72)
(ii) ..
(228)
~ (iii)
OMs
OMOM
OMOM
c£1 (229)
Elaboration of the MOM-protected intermediate (229) to the desired 3-
quinudidinol (151) was achieved by brief treatment with refluxing
concentrated hydrochloric acid and the desired 3-quinuclidinol (151) was
93
isolated in 83% yield after silica gel chromatography.
OMOM
CQ) (229)
12M Hel, WO°C, 15 mins
(Scheme 73)
(151)
We were left now to measure the optical rotation ([alo) of this compound and
compare it to the literature value for the (R)-3-quinuclidinol (151) of
+45.3°152,153. We were subsequently very satisfied to find that the 3-
quinuclidinol (151) derived from our bakers' yeast reduction product (222)
showed an optical rotation of +39.5° thus indicating (R)-geometry also. This
compound was indistinguishable from the authentic material by 1H and 13C
NMR. Furthermore this figure allowed us to calculate an enantiomeric excess
for the quinuclidinol derived from the bakers' yeast reduction product of 87%.
As we were careful not to enrich the optical purity of the compound during
the synthesis by making relevant checks on column fractions etc., we can also
state that the bakers' yeast reduction product (222) also shows an enantiomeric
excess of 87%. As we had already deduced the relative stereochemistry as being
cis and we now know the absolute stereochemistry at the 3 position of the
yeast reduction product (222) is (R) we can deduce the absolute stereochemistry
at the 4 position will be also (R) as shown in Figure 24.
94
(222)
(Figure 24)
Conclusion
In conclusion we can say that the bakers' yeast reduction of I-tert-butyl-4-
methyl 3-oxopiperidine-1,4-dicarboxylate (149) gives (3R, 4R)-l-tert-butyl-4-
methyl 3-hydroxypiperidine-1,4-dicarboxylate (222) in 81% chemical yield and
with an enantiomeric excess of 87% as shown in Figure 25.
5~ N I
BOC
(149)
Bakers' yeast/ sucrose/ ---..;..--~
water 35°C/24h
(Figure 25)
95
(222)
[a ]D23 -32.7
Yield 81%
e.e 87%
From the work carried out on the bakers' yeast reduction of piperidine-~-keto
esters so far we can say that in general bakers' yeast delivers hydrogen in a syn
fashion to the top face of the molecule as drawn in Figure 26, ie with the keto
functionality drawn on the left and the carboxylate functionality drawn on the
right, hydrogen is delivered into the page.
HO H .. l.~",C02R H ';
Bakers' ~ ..;
yeast ~
~ y
(Figure 26)
96
Chapter Four
Indolizidine Alkaloid Synthesis
97
Introduction to Indolizidines
Polyhydroxylated indolizidine alkaloids have recently gained considerable
synthetic interest as possible candidates for glycosidase inhibitor design. The
major driving force is attributable to the biological activity associated with two
such indolizidines, castano spermine (133)163 and swainsonine (132).164,165 The
compounds have been shown to inhibit various glycosidase and specifically
swainsonine (132) functions as a powerful inhibitor of lysosomol, jack bean a
mannosidase and the glycoprotein golgi mannosidase. Swainsonine (132) has
been also shown to inhibit the processIng of asparagIne linked
glycoproteins.166-169 Castano spermine (133) on the other hand is a potent
inhibitor of various glycosidases including lysosomol a-glucosidase, a- and ~
glucosidase in fibroblast extracts as well as inhibiting (3-xylosidaseI70-172 and
sucrase.173-175
The ability of such compounds to disrupt glycoprotein processing has resulted
in their use to modify glycoprotein biosynthesis and thus provide more insight
into the role of oligosaccharides in glycoprotein function.176-179 Recently,
castanospermine (133) and swainsonine (132) have been observed to inhibit
mestastasis of some cancers.180 Additionally castanospermine (133) has been
implicated as an inhibitor of the human immunodeficiency virus (HIV)
syncytium formationl80-186 and virus replication.187
For the purpose of this review a number of syntheses of these two molecules
will be described along with another important indolizidine alkaloid
allopumiliotoxin 339A (230). A further indolizidine alkaloid cyclizidine (231)
will also be described.
98
Castanospermine (133)
Castanospermine (133) [(15,65, 7R, 8R, 8aR)-1, 6, 7, 8-tetrahydroxyindolizidine]
has been isolated from the seeds of castanospermum australe 175 as well as
alexia leiopetala .188
Castanospermine (133)
(Figure 27)
The cOlnpound was first synthesised in 1984 by Bernotas and Ganem from D
glucose and from this synthesis the absolute configuration of the molecule was
determined.189 The synthesis involved treatment of the epoxide (232) with
sodium borohydride which facilitated loss of the trifluoroacetyl group and
subsequent attack by nitrogen on both carbons of the epoxide. One of the
resulting piperidines (233) was oxidised by the method of Swem (DMSO-oxalyl
chloride),190,191 condensed with lithio tert-butylacetate, hydrogenolysed and
treated with trifluoroacetic acid to furnish the corresponding lactam (235). The
lactam (235) was reduced with diisobutylaluminium hydride to give
99
castano spermine (133) which was identical to the natural material by 300MHz
IH NMR. The observed rotation was +7r with a literature value for the
natural material of +80 0 .175
Bno~ ~:C)CF3 HO
(i) Bno~,Bn (D)-Glucose -~ BnO N ~ BnO N --~ -Bn
OBn OBn
(232) (233)
1 (ii),(iii),
OH OH OBn OBn =-
BnO, :
(v) (iv) ...... .....
\1 " \1 ,- ,I " HO HO BnO 0
° (133) (235) (234)
Reagents: (i) NaBH4in ethanol (ii) Oxalyl chloride/DMSO (iii) Lithio tert-butylacetate (iv) H2 then TFA (Aq) (v) DffiAL-H
(Scheme 74)
Shortly after this synthesis was reported Hashimoto and co-workers reported
the synthesis of castanospermine (133) from D-mannose utilising a
100
double cyclisation reaction of the amino ester (241).192
OH .,.,0
> > X o \,,-HO
Castanospermine (133)
(241)
(Scheme 75)
In a forward sense succeSSIve selective protections of the diol functionalities
gave the alcohol (237). Moffatt oxidation193,194 and subsequent treatment of the
resulting aldehyde with potassium carbonate in methanol gave the 2,3 trans
aldehyde (238). This intermediate was converted to the corresponding oxime
followed by reduction with lithium aluminium hydride and the resulting
amine function protected as the benzyl carbamate (239). Partial hydrolysis of
this material followed by selective deprotection of the hydroxyl functions with
tosic acid and subsequent mesylation of the primary hydroxyl gave (240) which
was treated with sodium methoxide and cyclised to form an intermediary end
epoxide which readily isomerised in the presence of sodium methoxide to
produce the epoxide (240a). Oxidation of the primary alcohol of (240a), reaction
with tert-butyl lithioacetate, protection of the hydroxy I function and
deprotection of the amine gave the desired epoxy-amino-ester (241) in
101
preparation for the double cyclisation reaction.
D-Mannose
(240a)
",0
'X o
(241)
(iv) ....
(i)~~-t TBDMSO CHO
(237) (238)
! (ii)
,\ 0
(iii) ;;-'III(
NHZ
(240)
Reagents:
(i) BzCl/ pyridine;
TBDMSO ZN
H
(239)
TBDMSCl/ imidazole/ DMF; NaOH/ MeOH; DMSO / DCC/ pyridine; K2C03/ MeOH
(ii) H 2NOH.HCI/ NaHC03; LiAI~; ZCl/ THF(aq)
(iii) TsOH/ MeOH (aq); n-B1l.tNF; MsCl/ pyridine.
(iv) MeONa/ MeOH; (v) Cr03.2pyridine; lithiotert-butylacetate;
TBDMSCl/imidazole/DMF; H2 /Pd/C
(Scheme 76)
The resulting amine (241) was refluxed in methoxyethanol to give a mixture of
the indolizidines (242) and (243) which were readily separable by silica gel
102
chromatography. Finally (242) was reduced with borane-THF complex and
subsequent treatment with 6M HCl gave castanospermine (33). Similar
treatment of (243) gave 1-epicastanospermine (244).
(241)
Reagents:
OTBDMS OH
(i) 0 -...;..~' X \".
o o
(242)
l(ii)
OH
HO\ 1,1
o
+ X \". o
OH -: H PH .. ,
(243)
1 (ii)
o
QH OH - H ..
HO : -: ~ HO,m Castanospermine (33) 1-Epicastanospermine (244)
(i) Methoxyethanol! A (ii) Borane.THF then 6M HCl
(Scheme 77)
Ganem and co-workers reported the enantioselective synthesis of (+)
castano spermine (133) from (D)-glucose195 using a highly selective chelation
controlled Sakurai reaction of the type Keck,196,197 Danishefsky198,199 and
others200,201 have observed with a- and fl-alkoxy aldehydes. To this end the
aldehyde (245) which is available enantiomerically pure from D-glucose ~
oxidation of the protected (+ )-amino alditol (245),202 underwent the Sakurai
condensation with allyltrimethylsilane and titanium tetrachloride to furnish
the desired olefin (246). Ozonolysis followed by reduction with sodium
borohydride furnished the diol which was further elaborated to (+)-
103
castanospermine (133) by esterification with mesyl chloride followed by
hydrogenation/ cyclisation.
CHO BnO~lf Jjno~
OBn
(245)
HO (i) BnO __ ~: BnO ---
OBn
(246)
Reagents: (i) Ally ltrimethylsilane, TiC4
Castanospermine (133)
(ii) 03; NaB~/ ethanol; MsCI, Et3N; H2t Pdf C
(Scheme 78)
Of particular interest to the Knight group was the synthesis of (+)
castano spermine (133) reported by Sih and co-workers.203 This involves the
stereoselective reduction of pyrrolidine (3-keto ester (125) using Dipodascus sp.
o
c5co2Me I
BOC
(125)
Dipodascus sp . ..
(Scheme 79)
",OH .
Q""co2Me I
BOC
(126)
As was reported earlier in the text, Knight and co-workers achieved the
stereoselective reduction with 80% optical purity using baker's yeast.94 Sih was
able to achieve 99% optical purity using Dipodascus sp. and he attributes the
104
lower enantiomeric excess observed for the baker's yeast reduction being the
result of multiple enzymes operating with opposite stereochemical preferences
during the reaction.31
The initial reduction product (126) was protected as its silyl ether (247) and
transformed into the diester (248) by treatment with 2% trifluoroacetic acid
followed by removal of volatiles and treatment of the salt with methyl acrylate
and triethylamine. Acyloin condensation204 of (248) in the presence of
chlorotrimethylsilane led to the bis-trimethylsiloxy derivative (249). (249) was
smoothly converted to a mixture of (250) and (251) using excess DBU in
dichloromethane.
,OH t"
Q""C02Me (i)
~
I BOC
(126)
°
Reagents:
,OTBDMS t" ,
Q"'C02Me I
BOC
(247)
OTBDMS
(250) R=H (251) R=TMS
......
,OTBDMS t"
Q""C02Me (ii)
~
~C02Me (248)
~ (iii)
(iv)
(249)
(i) TBDMSClj imidazole (ii) CF3CO~; Et3N, methyl acrylate (iii) Na, TMSCI, I!l. (iv) DBU
(Scheme 80)
Both of these compounds were converted to (252) by reaction with LiN(TMSh
105
and chlorotrimethylsilane. Hydroboration of the intermediate followed ~
oxidation205 gave a mixture of (253), (254) and (255) which were readily
separable by chromatography. Desilylation led to (+)-castanospermine (133), 6-
deoxycastanospermine (255) and 6,7-diepicastanospermine (256) respectively.
o OTBDMS
(250) R=H (251) R=TMS
Reagents:
(i) TMSO ,..
(i) TMSCI/LiN(TMSh (ii) BH3, Mep; Me~O / il (iii) n-Bu4NF
TMSO
(252)
OTBDMS
(ii)
(Rl=TMS R2=TBDMS (253)
CO") ill Rl=R2=H Castano spermine (133)
+
24%
15%
R1=TMS R2=TBDMS (254)
(lii)( Rl=R2=H 6-Deoxycastanospermine (255)
1 R 0""
+ 32%
HO
R 1 = TMS R2= TBDMS (255)
(iii)( Rl=R2=H 6,7-Diepicastanospermine (256)
(Scheme 81)
106
Swainsonine (132)
Swainsonine [(1S, 2R, 8R, 8aR)-octahydro-1, 2, 8-indolizidinetriol)] has been
isolated from the fungus rhizoctonia legum in icola,164,165 the legume
leniginosus, the spotted locoweed astragalus lentiginosus206-208 and swainsona
canescens.166
.:-OH .
Swainsonine (132)
(Figure 28)
This alkaloid is believed to be the cause of locoism, a disease contracted by
animals upon ingestion of swainsonine containing plants.206-208 It has also
been suggested by Elbein that the physiological effects of the alkaloid may in
part be due to its ability to inhibit various enzymes including lysosomol u
mannosidase167 and mannosidase II.209 Lysosomol a-mannosidase is involved
in the cellular degradation of polysaccharides while mannosidase II is a key
enzyme in the processing of asparagine linked glycoproteins.210
107
Recent reports have indicated that swainsonine exhibits immunoregulatory
activity and this has led to it being considered as a possible candidate for cancer
chemother apy211,212.
Soon after its isolation the structure of the alkaloid was established166 and by
1983 Sharpless had reported its total synthesis at the 103rd Annual Meeting of
the Pharmaceutical Society of Japan in Tokyo. Soon afterwards Suami and co
workers published the total synthesis of the alkaloid starting from methyl 3-
acetamido-2, 4, 6-tri-O-acetyl-3-deoxy-a-D-mannopyranoside (258).213
> > >
Swainsonine (132)
(Scheme 82)
r OAc
Ac~J-O .... Ac
~ OAc OMe
(258)
Hydrolysis of this material (258) followed by O-deacety lation in methanolic
sodium methoxide, treatment with ethanethiol and tritylation with trityl
chloride in pyridine gave the dithioacetal (259). O-Benzylation of (259) followed
by removal of the O-trityl group afforded the tri-O-benzyl derivative (260). (260)
was converted to the pyrrolidine derivative (261) by tosylation followed by N-
108
deacetylation and subsequent cyclisation.
EtS
,OAc
Ac ..... J-O. Ac
~ OAc OMe
(258)
(261)
OBn ... ...
"'IOBn
(i) EtS
(iii) EtS
HO
(259) I (ii)
(260)
Reagents: (i) Hell A; AC20; MeONa, MeOH; EtSH; Trityl chloride/pyridine
(ii) Benzyl bromide/NaH/DMF; Mild acid (iii) Tosyl chloride/pyridine; NaOH/ 11
(Scheme 83)
II'IOH
OTr
The pyrrolidine derivative (261) was converted to the corresponding aldehyde
moiety and Horner-Emmons reaction with diethyl ethoxycarbonyl
methylphosphonate and sodium hydroxide gave a mixture of epimers which
could be successfully separated. Hydrogenation of the epimeric mixture over
Raney nickel afforded the saturated ester (262). Preparation of the lactam (263)
was achieved by heating the ester (262) in aqueous ethanolic potassium
hydroxide and subsequent reduction using lithium aluminium hydride and 0-
109
debenzylation213 gave (-)-swainsonine (132) which showed identical spectral
properties to that of the natural product.
EtS
~Bn --
"'IOBn
(261)
OR ... ... --"'lOR
(264) R=Bn (132) R=H
~
9Bn (i) .. --... "'IOBn
(262)
J (ii)
9 Bn ...
(iii) -"'JOBn
a (263)
Reagents: (i) HgCl21 CaCD.3; diethyl ethoxycarbonylmethylphosphonate/NaH; H2/Raney nickel
(ii) KOH, ethanol, fl., 6 days (iii) LiAIH4; Pd(OHhl C, cyclohexene
(Scheme 84)
At the same time Takaya and co-workers published the synthesis of
swainsonine (132) starting from (D)-mannose (236).215 Methyl-6-O-benzoyl-2,3-
O-isopropylidene-a-D-talopyranoside (265) derived from D-mannose according
to the method of Evans216 was mesylated and deprotected as shown in Scheme
85. Reaction of the intermediate (267) with sodium azide in DMF followed by
protection with 2,2-dimethoxypropane and alkaline hydrolysis gave the azido
110
derivative (268) in almost quantitative yield. Oxidation of the primary alcohol
followed by Wittig reaction with (methoxycarbonyl-methylidene) triphenyl
phosphorane gave the vinyl ether which was hydrogenated and cyclised to the
corresponding amide (269). The amide was further elaborated to swainsonine
(132) by demethylation with boron trichloride and subsequent treatment with
sodium cyanoborohydride. Again the final product was spectroscopically
identical to the natural product.
HOG- Bill~ Bill~ o HO 0 (i) MsO ~
OHHO OH ~~~ era ~ o 0
HO OMe OMe
(236) (265) (266)
! (ii) HOB Bill~ 0
(iii) MsO 0
0 (iv) o~ .... ..... OHHO
N3 OMe OMe
(268) (267)
! (v) Reagents:
OH (i) Mesyl chloride, pyridine :- (ii) Trifluoroacetic acid . "
"'IOH (iii) NaN3, DMF; 2,2 dimethoxypropane;
hydrolysis (iv) Sulphur trioxide.pyridine: DMSO: Et3N;
Swainsonine (132) (methoxycarbonylmethylidene)tnphenyl-phosphorane; H2/ Pd
(v) BH3.THF; BCI~ NaBH3CN
(Scheme 85)
111
Hart and co-workers adopted a different approach to the synthesis of the
alkaloid in that instead of using carbohydrate precursors they utilised an a
acylamino radical approach.217
(183)
AC~O ..... ,OAc (i) ---l.,.
o N 0 H
(270)
(ii) .,
Ph
(v) (iv) ''''OAc .. . ... OAc, .......... t---
AcO).-.-{ ... ,OAC
o~NAo
(272)
(iii)
o o (277)
(vi)
''''OH
R1=Ph, R2=H (275)
R1=H, R2=Ph (276)
Ph X=OH (273) X=SPh (274)
Swainsonine (132)
Reagents: (i) Acetyl chloride, NHy Acetyl chloride (ii) Ph3P, DEAD, PhC=CCH2CH2CH20H (271) (iii) NaBH4r MeOH; AC20, Et~, DMAP; n-Bu~, PhSSPh (iv) n-Bu3SnH, AlliN, PhH (v) °3, MeOH; Me2S; NaBHt, MeOH (vi) Me3CCOCI, DMAP, pyridine; NH3, MeOH; Me3CCOCI, DMAP,
pyridine, Tf20; KOAc, 18-crown 6, DMF; AC20, Et~, DMAP; (p-MeOC6H4PS02; Raney Ni, EtOH; MeNH2
(Scheme 86)
112
The imide (270) was prepared by the sequential treatment of D-tartaric acid
(183) with acetyl chloride, ammonia and acetyl chloride. Treatment of the
imide (270) with a mixture of triphenyl phosphine, diethylazodicarboxylate
(DEAD) and the acetylenic alcohol (271) afforded the tartarimide (272) in close
to quantitative yield. Reduction of the intermediate gave the carbinol lactam
(273) as a mixture of diastereomers. The lactam was subsequently treated with
diphenyl disulphide in the presence of tri-n-butylphosphine to furnish the
desired radical precursor (274). Reaction of (274) with tri-n-butyltin hydride in
the presence of the radical initiator azo-bis-isobutyronitrile gave the epimeric
mixture (275)/(276). The mixture was ozonised and reduced with sodium
borohydride to furnish the indolizidine (277) which was further elaborated to
swainsonine (132) as shown in Scheme 86.
Allopumiliotoxin 339A (230)
Several members of the pumiliotoxin A class of amphibian alkaloids display
significant cardiotonic activity.218-222 Recent pharmacological studies
demonstrate that pumiliotoxin B enhances sodium influx by binding to a
unique modulatory site on the voltage dependant sodium channe1.223,224 This
interaction has been shown to stimulate phosphoinositide breakdown with the
effect on this secondary messenger system being ultimately expressed at
cardiotonic and myotonic activities.
113
The most complex and rare members of the pumiliotoxin A group are the
allopumiliotoxins225,226 which contain oxidation at both C-(7) and C-(8) of the
indolizidine ring.
Allopumiliotoxin 339 A (230) is the only pumiliotoxin A alkaloid to be more
effective at stimulating both sodium influx and phosphoinositide breakdown
than pumiliotoxin B.224
Allopumiliotoxin 339A (230)
(Figure 29)
Overman and co-workers have published the total synthesis of this
molecule228 which involves the combination of the proline derived aldehyde
(279) with the side chain alkyne (278). Addition of the alkynyl derivative of
(278) to the a-benzyloxyaldehyde (279) gave mainly (280) which was further
treated with silver triflate to yield the cyclopentaoxazine (281) in high yield.
Cyclisation to give the indolizidine skeleton (282) was achieved with tosic acid
and sodium iodide in aqueous acetone. Elaboration to the natural product (230)
was achieved by de-iodination followed by cleavage of the benzyl ether. The
114
isolated product was indistinguishable from the natural toxin by TLC and l3C
NMR.
H
+
':: : ":.
(278)
CHO
(279)
x
<- OH , OR
",0 ~.
(i)
OH (iii) ~
OH
(282) R=OBn, X=I
(230) R=X=H
....
Reagents: (i) n-BuLi (ii) AgOS02CF3 (iii) TsOH, NaI (iv) n-BuLi; MeOH; Li, NH3
(Scheme 87)
115
(280)
I (iil
.. .. o 0
X
(281) -~ 0
X
Cyclizidine (231)
An indolizidinediol with an unusual a,~:y,()-unsaturated cyclopropyl side
chain has been isolated from a new streptomyces species NCm 11649 which
itself has been isolated from hedgerow soil samples in the Greater Manchester
area. In 1982 the crystal structure was determined by Sim and co-workers229 but
the compound has not yet been synthesised by chemical methods. Interestingly
the compound shows non-selective immunostimulatory properties and
furthermore its acetate causes a reduction in the frequency of cultured heart
cells, an effect seen with certain (3-blocking drugs.
Cyclizidine (231)
(Figure 30)
116
We were particularly interested in the indolizidine alkaloid Cyclizidine (231)
by virtue of the fact that it has not yet been synthesised in the laboratory. We
envisaged the use of the piperidine ~-hydroxy ester (167) derived from baker's
yeast reduction as a chiral building block in our proposed synthesis. One such
retrosynthetic analysis is shown in Scheme 88 which is one of our many ideas
of how the total synthesis of Cyclizidine (231) may be accomplished.
OH __ ~> O~ ' ..
(231) (285) '':::::'-0
"ltOH < Op4 < Op4
' .. ' .. ' .. (289) ';.---Op2 (288) ';.---Op2 (287) -:'--Op2
~ Opl -:: H -:.
"1
,J'O . > > (292)
Op2
(290) orZ (291) Op2
{j, OH Opl 0 -:: -:: O .. ,'C02Me O .. ,'C02Me < <
NBOC NBOC
(167) (294) (293)
(Scheme 88)
117
In a forward sense protection of the initial yeast reduction product (167) as its
silyl ether (294)117 followed by Grignard reaction of the ester functionality with
methylmagnesium bromide should afford the corresponding methyl ketone
(293).230 Treatment of this ketone (293) with the anion produced by the action
of n-butyllithium on prop argyl alcohol protected as its silyl ether should then
form the corresponding acetylene (292). It is hoped that the two chiral centres
formed by the baker's yeast will direct the nucleophilic attack as drawn.
Hydrogenation of the acetylene (292) using palladium on barium sulphate
poisoned with quinoline231 should allow selective reduction of the triple bond
to produce the corresponding cis-olefin (291). It is envisaged that the ally lie
alcohol (291) will then be epoxidised in a stereoselective manner using
Sharpless methodology232-236 followed by protection of the free hydroxyl
function to furnish the differentially protected epoxy-triol (290). Deprotection
of the amine function should result in attack by the free amine onto the
epoxide thus forming the indolizidine skeleton (289). Mitsonobu inversion237
of the C-(2) hydroxyl followed by protection should then furnish the desired
indolizidine skeleton (288) with the correct stereochemistry of the target
molecule Cyclizidine (231). Deprotection of the C-(8) hydroxyl followed by
dehydration and subsequent stereoselective epoxidation should yield the epoxy
derivative (286). In order to complete the synthesis the hydroxyl function on
the C-(3) side-chain will be oxidised to the corresponding aldehyde (285)238 and
the side chain (284) introduced in one piece in a Wittig type reaction239-240 to
furnish Cyclizidine (231).
We realised that much work will have to be carried out on this synthesis and
realised that some of our ideas may only look good on paper. However, we are
confident that the general synthetic ideas are of sound judgement and to this
end we decided to undertake model reactions to prove that the synthetic
scheme is viable. For the purpose of this project we decided to model the ring
closure reaction of the amine group attacking the epoxide to form the
118
indolizidine ring structure to firstly see if the reaction would take place and if
so to determine whether or not it would be stereoselective. To this end work
was undertaken in the synthesis of the required amino epoxide (295) which we
intended to cyclise to give the indolizidine skeleton (296).
o
(295) (296)
(Scheme 89)
Protection of 2-piperidineethanol (297) as its benzyl carbamate was achieved
using Schotten Baumann methodologylOO and we were able to isolate the
desired protected material (298) in high yield. This was subsequently oxidised
to the corresponding aldehyde (299) using the Parikh-Doering procedure of
DMSO, sulphur trioxide-pyridine complex and triethylamine.238,241-246 We
were pleased to isolate the desired aldehyde (299) in 82% yield after column
chromatography. Wittig reaction of the aldehyde (299) using the stabilised ylide
methyltriphenylphosphorylideneacetate (300) gave the a,~-unsaturated ester
(301). Reduction of the ester moiety to the corresponding alcohol was achieved
using diisobutylaluminium hydride in toluene at _78°C116 and the desired
ally lie alcohol (302) was isolated in 87% yield after purification by silica gel
chromatography. Protection of the hydroxyl function was performed by the
119
action of tert-butyldimethylsilyl chloride117, triethylamine and DMAp118 and
the corresponding sily! ether (303) was isolated in a yield of 79%.
OH
(297)
(303)
Reagents:
(i) ---'~
(v) .... OTBDMS
(298)
(302)
(i) Benzyl chloroformate/NaOH
OH
(ii) r'I ~ ~N~o
I
(iv)
OH
Z
(299)
(iii)
•
(301)
(ii) DMSO, sulphur trioxide. pyridine complex, Et~ (iii) Ph~=CHC02Me (300) (iv) DffiAL-H in toluene (v) TBDMSCI, Et~, DMAP
(Scheme 90)
Epoxidation of this moiety (303) was achieved using met a-chloroperoxybenzoic
acid247 and the epoxide (304) was isolated as a mixture of inseparable
diastereomers. We were disappointed by the fact that we were unable to
separate these diastereomers and found that this caused problems in the final
cyc1isation step. Deprotection of the amine functionality by hydrogenation over
5% palladium on carbon248,249 followed by stirring for 24 hours in methanol
led to a complicated mixture of diastereomers which made structure
elucidation of the product virtually impossible. To this end we decided to
120
adopt a different approach to the preparation of the amino-epoxide (295) in the
hope that more stereochemical control could be achieved.
(303)
Reagents;
(i) m-CPBA
(i)
OTBDMS
(ii) H2/5% Pd on C; MeOH 36h
(Scheme 91)
OTBDMS
(304)
?{ Complicated mixture of } products, unable to
• identify.
2-Piperidinemethanol (177) was protected as its tert-butyl carbamate using di
tert-butyl dicarbonate and triethylamine98 and the desired protected derivative
(305) was isolated in 80% yield. Oxidation of the hydroxyl function was
achieved as before by using the Parikh-Doering procedure of DMSO, sulphur
trioxide-pyridine complex and triethylamine241-246. We were pleased to isolate
the desired aldehyde (306) in 74% yield after column chromatography.
Treatment of the aldehyde (306) with the anion generated by the action of 11-
butyl lithium on O-tert-butyldimethylsilyl-propyn-1-01 (307) led to the
acetylenic derivative (308) as largely a single diastereomer by 13(: NMR which
121
was selectively reduced to the corresponding cis-olefin (309) by hydrogenolysis
over palladium on barium sulphate poisoned with quinoline231. We
envisaged the use of Sharpless methodology232-236 would need to be adopted to
stereoselectively epoxidise the allylic alcohol. However we were pleased to
isolate the desired acetoxy epoxide (310) as a single diastereomer after treatment
with met a-chloroperoxybenzoic acid 247 followed by protection of the free
hydroxyl function as its acetate (acetic anhydride/pyridine) to prevent Payne
rearrangement from occurring2S0.
QOH (i) QOH (ii) ~ ~
I I
H BOC
(177) (305)
OTBDMS OTBDMS
(v) (iv) 0 .... ....
OAe OH
(310) (309)
Reagents:
(i) Di-tert-butyl dicarbonate (ii) DMSO, sulphur trioxide. pyridine complex, Et~ (iii) TBDMSOCHz-C=C-OH (307), n-BuLi (iv) H21 Pd on BaS04f quinoline (v) m-CPBA; AC20, pyridine
(Scheme 92)
~O I BOC
(306)
!(iiil OTBDMS
OH
(308)
We were agaIn In a position to model the cyclisation of the free amIne
function onto the epoxide in an attempt to produce the indolizidine ring
122
structure. Removal of the tert-butyl carbamate was smoothly achieved USIng
trifluoroacetic acid123 and the free base (311) formed by neutralisation of the
reaction mixture cyclised to form the desired indolizidine (312) by stirring in
methanol for 36 hours. lH NMR indicated that the product isolated after silica
gel chromatography was extremely pure and 13C NMR indicated the presence
of a single diastereomer.
OTBDMS OH OAe
o (i)
---~ (ii)
-..:......:....-~
OAe
(310) (311) (312)
Reagents:
(i) Trifluoroacetic acid (ii) MeOH, room temp, 36h
(Scheme 93)
We were excited at our findings and decided to undertake NOE experiments in
the hope of elucidating the relative stereochemistry of the product (312).
123
OAc
(312)
(Figure 31)
Irradiation at b5.15 (l-H) led to an enhancement of signal at b3.58-3.72 (3-H) and
also at b1.97 (8-HAHB) which indicates a syn arrangement of the C-(1)-acetate
and the C-(3) side chain.
Irradiation at b4.31 (2-H) led to an enhancement of signal at b3.58-3.72 (3-H),
b3.29-3.38 (8a-H) and also at b4.24 (5-HAHB) which indicates a syn arrangement
of the C-(2) hydroxyl to the C-(3) side-chain and an anti arrangement of the C
(2) hydroxyl to the bridge proton. This means the functional groups at C-(l),
C-(2) and C-(3) are all syn to each other and anti to the bridge proton (8a-H).
Irradiation at b3.29-3.38 (8a-H) led to an enhancement of signal at b4.31 (2-H),
b1.97 (8-HAHB), and b4.24 (5-HAHB) confirming the anti arrangement of the C
(2) hydroxyl to the bridgehead proton 8a-(H).
Irradiation at M.24 (5-HAHB) led to an enhancement of signal at b2.79 (5HAHB)
and also at b1.97 (8-HAHB).
Irradiation at b1.97 (8-HAHB) led to an enhancement of signal at b1.25-1.35 (5-
HAHB).
124
From these experiments we are able to assign the relative stereochemistry of
the diastereomer (312) produced from the cyciisation as shown in Figure 32.
H
(Figure 32)
-~ ",
. .
" -'
" -,' "r
\ 110%1 -~OH
To follow on from these rather pleasing results we decided to substitute our
yeast reduction product (167) for the protected 2-piperidinemethanol
125
derivative (305) used in the previous synthesis. We were disappointed to find
that preliminary results of the addition of the anion of O-tert
buty ldimethylsily 1-propyn-1-ol (307) onto the piperidine-~-hydroxy ester (167)
led to the elimination of the hydroxyl function to form the corresponding
olefin (314) presumably by base extraction of the proton a- to the ester function.
x (167)
(Scheme 94)
OP 0
~ N
'BOC
(313)
(314)
OTBDMS
However this reaction was only attempted on one occasion and time did not
permit further study in this area.
126
Chapter Five
Experimental
127
General Details -
Melting points were determined on a Kofler hot stage apparatus and are
uncorrected. Optical rotations are determined using an Optical Activity AA-I0
polarimeter. Infrared spectra were recorded using a Perkin-Elmer 1600 series
Fourier transform spectrometer using neat films unless otherwise stated. 1 H NMR
spectra were determined using a Perkin-Elmer R32 (90 MHz), a Bruker WM-250
(250 MHz), a Jeol EX-270 (270 MHz) or a Bruker AM-400 (400 MHz). 13e NMR
spectra were recorded using a Jeol EX-270 (270) operating at 67.8 MHz, a Bruker
WM-250 (250 ) operating at 62.5 MHz or a Bruker AM-400 (400) operating at 100.1
MHz. Dilute solutions in deuterochloroform were used throughout unless
otherwise stated and tetramethylsilane was used as an internal standard
throughout. All J values are in Hz. Mass spectra were determined using either an
A. E. I. MS902 or VG 7070E spectrometer. All molecular formulae, quoted both for
molecular ions (M +) and fragments, are accurate to ± 3 ppm.
Tetrahydrofuran was dried over potassium and benzophenone and distilled as
required. Ether, toluene and benzene were dried over sodium. Dichloromethane,
dimethyl formamide, diisopropylamine, dimethyl sulphoxide and chloroform
were dried over calcium hydride and distilled onto 4A molecular sieves. Pyridine,
triethylamine and diisopropylethyl amine were dried over potassium hydroxide.
Oxalyl chloride was freshly distilled before use. Acetonitrile was dried over
phosphorus pentoxide and distilled onto 4A molecular sieves. Methanol was dried
using magnesium methoxide and distilled onto 4A molecular sieves. Ethanol was
dried using magnesium ethoxide and distilled onto 4A molecular sieves
All organic solutions were dried over anhydrous magnesium sulphate. Sorbsil
silica gel was used throughout.
128
N-(BenzyloxycarbonyD-4-aminobutyric acid (137)
NH2~C02H
(136)
Benzyl chloroformate (136) (36.4 g, 214 mmol) and sodium hydroxide (8.5 g, 214
mmol) in water (100 ml) were simultaneously added to a stirred, ice-cooled
solution of 4-aminobutyric acid (20 g, 194 mmol) and sodium hydroxide (7.8 g, 194
mmol) in water (100 ml). The reaction mixture was warmed to room temperature,
stirred for 16h, washed with ether (50 ml) acidified to pH 1 with 2M aqueous
hydrochloric acid then extracted with dichloromethane (3 x 150 ml). The combined
organic extracts were washed with brine (30 ml) and concentrated in vacuo to give
the title compound (137) (40.5 g, 88%) as a white solid, m.p 110-112°C, Vrnax 1700,
1710 and 3440 em-I, ()H (90) 1.58-1.97 (2H, m, NHCH2CH2), 2.33 (2H, t, J 7.5,
CH2C02H), 3.20 (2H, td, J 7.5 and 6, NHCH2), 5.60 (2H, s, PhCH2), 7.30 (SH, s,
C6Hs) and 9.84 (1H, br s, C02H).
MethyI6-[(benzyloxycarbonyDamino)-3-oxohexanoate (138)
HNZ~C02H
(137)
HNZ~C02Me o
(138)
l,l'-Carbonyl diimidazole (4.1 g, 25 mmol) was added to a stirred solution of the
protected amino-acid (137) (5 g, 21 mmol) in dry dichloromethane (l00 ml). The
reaction mixture was stirred at room temperature for 16h, and subsequently
added to a stirred solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum'S acid)
(3.6 g, 25 mmol) and pyridine (2 g, 25 mmol) in dichloromethane (l00 ml) at DoC.
After 90min at O°C the reaction mixture was warmed to room temperature, stirred
for Ih diluted with dichloromethane (150 ml) then washed with 2M citric acid (2 x
129
50 ml) and brine (50 ml). The organic phase was dried and concentrated ill vacuo.
The residue was dissolved in methanol (100 ml), refluxed for 3h and concentrated
in vacuo. Chromatography of the residue over silica gel eluting with
dichloromethane : ethyl acetate (9:1) gave the title compound (138) (4.95g, 80%) as
a clear colourless oil, RF 0.65, Umax 1700, 1740, 2940 and 3440cm-1, ~H (90) 1.60-
1.95 (2H, m, CH2CH2C=O), 2.555 (2H, t, J 7, CH2C=O), 3.15 (2H, m, NHCH2), 3.40
(2H, s, O=CCH2C=O), 3.70 (3H, s, CH3C02), 5.00 (lH, br s, NH), 5.10 (2H, s,
PhCH2) and 7.35 (5H, s, C6Hs).
Methyl6-[(benzyloxycarbonyl)amino]-2-diazo-3-oxohexanoate (139)
HNZ~C02Me o
(138)
HNZ
o
(139)
Triethylamine (1.45 g, 14.3 mmol) was added in a single portion to an ice-cooled
stirred solution of the f3-keto-ester (138) (1.4 g, 4.8 mmol) and p
(carboxybenzene)sulphonyl azide (1.2 g, 5.3 mmol) in acetonitrile (20 ml). The
reaction mixture was warmed to room temperature, stirred for 90 minutes, diluted
with dichloromethane (200 ml) then washed with saturated aqueous sodium
hydrogen carbonate (40 ml) and brine (40 ml). The combined organic extracts were
dried and concentrated in vacuo. Chromatography of the residue over silica gel
eluting with dichloromethane : ethyl acetate (9:1) gave the title compound (139)
(1.28g, 84%) as a colourless oil, RF 0.45, umax 1710, 2140, 3000 and 3440cm-1, OH
(90) 1.65-2.00 (2H, m, NHCH2CH2), 2.85 (2H, t, J 7, NHCH2CH2CH2), 3.18 (2H, m,
NHCH2), 3.78 (3H, s, CH3C02C), 5.08 (2H, s, PhCH2) and 7.35 (5H, s, C6HS)'
130
(±)-1-Benzyl-2-methyl-3-oxopiperidine-1,2-dicarboxylate (140)
HNZ
o
(139) (140)
Rhodium (IT) acetate dimer (22 mg, 0.06 mmol) was added to a solution of the a
diazo-~-keto-ester and the resulting suspension immediately immersed in an oil
bath pre heated at 90°C. The reaction mixture was heated at this temperature for
30 minutes and cooled. The resulting solution was filtered through kieselguhr and
concentrated in vacuo. Chromatography of the residue over silica gel eluting with
dichloromethane : ethyl acetate (9:1) gave the title compound (140) (178mg, 49%)
as a colourless oil, RF 0.85, Vmax 1710 and 2960cm-1, ~H (90) 1.73-2.15 (2H, m,
NCH2CH2), 2.30 and 2.67 (2H, 2t, J 6.4 and 6.1, NCH2CH2CH2), 3.32-3.65 (lH, m,
6-Hax), 3.71 and 3.77 (3H, 2s, CH3C02C), 3.80-4.20 (lH, m, 6-Heq), 5.17 (2H, s,
PhCH2) and 7.35 (5H, s, C6HS).
EthyI2-pyrrolidinone-N-acetate (144)
('Ao I
H
(143) (144)
2-Pyrrolidinone (143) (85 g, 1 mol) was added to a rapidly stirred suspension of
molten sodium (23 g , 1 mol) in refluxing toluene (600 ml). Heating was continued
for 1h after which time ethyl bromo acetate (167 g, 1 mol) was introduced dropwise
over a period of 20min. The reaction mixture was heated for 1h, cooled, filtered
and concentrated in vacuo. The residue was distilled under reduced pressure (b.p.
131
127°C j 0.1 mmHg) to give the title compound (144) (142g, 83%) as a colourless
oil, Vmax 1740 em-I, f>H (270) 1.28 (3H, t, J 7.25, CH3CH2DlC), 2.02-2.12 (2H, In,
CH2CH2C=O), 2.39 (2H, t, J 8, CH2CH2C=O), 3.50 (2H, t, J 7 , N-CH2CH2), 4.05
(2H, s, NCH2C02Et) and 4.19 (2H, q, J 7.25, CH3CH202Q, f>C (68.5) 13.50 (CH3),
17.30 (CH2), 29.65 (CH2), 43.36 (CH2), 47.03 (CH2), 60.52 (CH2), 168.01 (C) and
174.88 (C), mj z 171 (20%, M), 125 (5, M-EtO), 98 (100, M-CDlEt), 84 (19, M
CH2C02Et), 70 (26, M- NCH2C02Et) and 68 (3, M-O-CH2C02Et), [Found: M,
171.0900. CSH13N03 requires M, 171.0895].
3-Azahepta-l,7- dioic acid hydrochloride (145)
(144)
CC02H
N~COH I 2
H.HCI
(145)
A solution of the pyrrolidine (144) (120 g, 702 mmol) in aqueous 6M hydrochloric
acid (800 ml) was refluxed for a period of 48h. The resulting solution was cooled
and concentrated in vacuo. The residue was disssolved in methanol (400 ml) and
concentrated in vacuo. This procedure was repeated to give the title compound
(145) (115g, 83%) as a colourless gum, f>H (400) (D20) 1.67 (2H, m, CH2CH2C02H),
2.21 (2H, t, J 7.2, CH2CH2C02H), 2.86 (2H, t, J 7.80, NCH2CH2) and 3.67 (2H, s,
NCH2C02H), f>C (100) (D20) 23.13 (CH2), 33.03 (CH2), 49.24 (CH2), 49.79 (CH2),
171.22 (C) and 179.06 (C), mj z 144 (9%, M-HCI-OH), 143 (50, M-HCI-H-OH), 116
(7, M-HCI-CDlH), 99 (51, M-HCI-C02H-OH), 98 (100, M-HCI-C02H-OH-H), 71 (8,
M-HCI-C02H-C02H) and 70 (81, M-HCI-C02H-C02H-H), [Found: M-HCI-OH,
144.0660. C6HION03 requires M-HCI-OH, 144.0660].
132
Dimethyl3-azahepta-1,7- dicarboxylate hydrochloride(146)
(145) (146)
The diacid (145) (88 g, 446 mmol) was dissolved in methanol (500 ml) to which
acetyl chloride (50 ml) had been added. The resulting solution was refluxed for 5h,
cooled and concentrated in vacuo to give the title compound (146) (80.3 g, 80%) as
a colourless oil, 'Umax 1728, 1741 and 3360 em-I, bH (400) (CD30D) 2.01-2.16 (2H,
ill, CH2CH2C02Me), 2.57 (2H, t, J 7.3, CH2CH2C02Me), 3.24 (2H, t, J 7.7,
NCH2CH2), 3.71 (3H, s, CH3C02C), 3.87 (3H, s, CH3C02C), 4.10 (2H, s,
NCH2C02Me) and 5.48 (lH, br s, NH), be (l00) (CD30D) 18.84 (CH2), 27.21 (CH2),
31.56 (CH2), 49.00 (CH2), 52.44 (CH3), 53.70 (CH3), 168.02 (C) and 174.40 (C), mj z
189 (3%, M-HCI), 130 (89, M-C02Me), 99 (7, M-C02Me-Me), 98 (100, M-C02Me
Me-H), 71 (4, M-C02Me-C02Me), 70 (46, M-COzMe-C02Me-H) and 59 (17,
C02Me), [Found: M-HCI, 189.0992. CSHISN04 requires M-HC1, 189.1001].
Dimethyl N-(ferf-butyloxycarbonyl)-3 .. azahepta .. 1,7- dicarboxylate (147)
(146) (147)
Di-tert-butyl dicarbonate (32 g, 146 mmol) was added dropwise to a solution of the
diester (146) (30 g, 113 mmol) and triethylamine (14.8 g, 146 mmol) in
dichloromethane (200 ml) at room temperature. The reaction mixture was stirred
for 16h, diluted with dichloromethane (200 ml), washed with 2M aqueous citric
133
acid (2 x 30 ml), saturated aqueous sodium chloride (30 ml), and dried. The
resulting solution was passed through a pad of silica gel and concentrated in vacuo
to give the title compound (147) (32.7 g, 85%) as a colourless oil, Umax 1668, 1725
and 1738 em-I, bH (400) 1.23 (9H, s, (CH3hCO), 1.65 (2H, tt, J7.3 and 6.8
CH2CH2C02Me), 2.15 (2H, t, J 7.3, CH2CH2C02Me), 3.13 (2H, t, J 6.8, NCH2CH2),
3.46 (3H, s, CH3C02), 3.52 (3H, s, CH3C02) and 3.70 (2H, s, NCH2C02Me), be
(100) 23.35 (CH2), 27.89 (CH3), 30.76 (CH2), 39.87 (CH2), 47.45 (CH2), 50.89 (CH3),
51.29 (CH3), 79.76 (C), 155.67 (C), 170.02 (C) and 173.00 (C), mj z 188 (14%, M
BOC), 158 (8, M-BOC-Me-Me), 157 (8, M-BOC-OMe), 101 (l6, BOC), 70 (l5, M
BOC-C02Me-C02Me), 59 (l5, C02Me) and 57 (l00, (CH3hC), [Found: M-BOC,
188.0884. C9H14N04 requires M-BOC, 188.0923].
(±)-1-tert-Butyl-2-methy13-oxopiperidine-1,2-dicarboxylate (148) and
(±)-1-tert-butyl-4-methyl 3-oxopiperidine-1,4-dicarboxylate (149)
C;:2Me .... 0°+ CX:02Me N e02Me N
I I I BOC BOC BOC
(147) (148) (149)
Potassium tert-butoxide (9.7 g, 87 mmol) was added in portions over 10min to an
ice-cooled solution of the N-protected diester (147) (25 g, 87 mmol) in dry toluene
(200 ml). Mter a further 10min the reaction mixture was acidified to pH3 with 2M
aqueous citric acid, the organic layer separated and the aqueous phase further
extracted with dichloromethane (3 x 100 ml). The organic phases were combined,
washed with saturated aqueous sodium chloride (50 ml), dried and concentrated
ill vacuo. Chromatography of the residue over silica gel eluting with
dichloromethane : ethyl acetate (9:1) gave the title compound (148) (l0.4 g, 47~i,) as
134
a colourless oil, RF 0.9, umax 1662, 1690 and 3361 em-I, bH (270) 1.47 (9H, s,
(ClthC), 2.32-2.40 (2H, m, NCH2CH2), 3.49 (2H, t, J 6, NCH2CH2), 3.78 (3H, s,
CH3C02C), 4.03 (2H, s, NCH2C=0) and 12.00 (lH, s, OH), bC (68.5) 21.91 and 2.38
(CH2), 28.1 and 28.10 (CH3), 39.90 and 41.23 (CHV, 44.96 and 45.53 (CHV, 51.51
(CH3), 79.37 and 80.34 (C), 96.58 and 98.46 (C), 154.03 and 154.37 (C), 166.97 (C)
and 172.99 (C), mj z 156 (6%, M-BOC), 125 (13, M-BOC-OMe), 101 (3, BOC), 97 (8,
M-BOC-C02Me),59 (10, C02Me) and 57 (lOO, (CH3hC), [Found: M-BOC, 156.0634.
C7HION03 requires M-BOC, 156.0661] and the title compound (149) (6 g, 27%) as
a colourless oil, RF 0.8, Umax 1698, 1740 and 3407 em-I, bH (270) 1.44 (9H, s,
(ClthC), 1.95-2.08 (2H, m, NCH2CH2CH2), 2.42-2.60 (2H, m, NCH2CH2CH2),
3.28-3.52 (lH, m, 6-Hax), 3.79 (3H, s, CH3D2C), 3.86-4.10 (lH, m, 6-Heq) and 11.12
(lH, br s, OH), ()C (68.5) 22.32 (CH2), 26.52 (CH2), 27.87 (CH3), 37.82 (CHv, 53.05
(CH3), 81.17 (C), 107.92 (C), 154.79 (C), 167.40 (C) and 169.40 (C), mj z 257 (2%, M),
156 (10, M-BOC), 125 (18, M-BOC-OMe), 97 (6, M-BOC-C02Me), 59 (11, C02Me)
and 57 (10, (CH3hC), [Found: M, 257.1235. CI2HI9NOS requires M, 257.1263].
Diethyl 3-azahepta-1,7-dicarboxylate hydrochloride(208)
CC02H
N/"...CO H I 2
H.HCl
(145)
eC02E!
N/'..CO Et I 2
H.HCI
(208)
The diacid (145) (105 g, 532 mmol) was dissolved in ethanol (500 ml) to which
acetyl chloride (50 ml) had been added. The resulting solution was refluxed for 5h,
cooled and concentrated in vacuo to give the title compound (208) (113 g, 84%) as a
pale yellow oil, Vmax 1735, 1738 and 3290 em-I, ()H (400) (CD30D) 1.28 (3H, t, J 7,
CH3CH2D2.C), 1.35 (3H, t, J 7, CH3CH2D2.C), 2.10 (2H, m, CH2CH2C02Et), 2.55
(2H, t, J 7, CH2CH2C02Et), 3.22 (2H, t, J 6.5, NCH2CH2), 4.05 (2H, s, NCH2C02Et),
135
4.16 (2H, q, J 7, C02CH2CH3), 4.32 (2H, q, J 7, C02CH2CH3) and 4.88 (lH, br s,
NH), bC (100) (CD30D) 14.39 (CH3), 14.54 (CH3), 22.27 (CH2), 31.88 (CH2), 48.80
(CHV, 58.22 (CH2), 61.65 (CH2), 63.50 (CHV, 167.49 (C) and 173.94 (C), mj z 217
(3%, M-HCI), 172 (5, M-EtO), 144 (89, M-C02Et), 115 (14, M-C02Et-Et), 99 (22, M
C02Et-OEt) and 84 (18, M-C02Et-C02Et-H), [Found: M-HCI, 217.1002.
CloHl9N04 requires M-HC1, 217.1314].
Diethyl N-(methoxycarbonyD-3-azahepta-l,7-dicarboxylate (209)
(208) (209)
Methyl chloroformate (8.2 g, 87 mmol) was added dropwise to a solution of the
diester (208) (20 g, 78 mmol) and triethylamine (8.8 g, 87 mmol) in
dichloromethane (200 ml) at O°C. The reaction mixture was warmed to room
temperature, stirred for 16h, diluted with dichloromethane (200ml), washed with
aqueous 2M hydrochloric acid (2 x 30 ml), saturated aqueous sodium chloride (40
ml), and dried. The resulting solution was passed through a pad of silica gel and
concentrated in vacuo to give the title compound (209) (15.2 g, 70%) as a colourless
oil, Vmax 1670, 1732 and 1736 cml, bH (400) 1.07 (3H, t, J 7, CH3CH202CCH2CH2),
1.11 (3H, t, J 7, CH3CH2D2CCH2N), 1.55-1.75 (2H, m, CH2CH2C02Et), 2.08-2.28
(2H, m, CH2CH2C02Et), 3.16 and 3.19 (2H, 2 x t, J 7 and 7, NCH2CH2), 3.46 and
3.51 (3H, 2xs, CH3C02CN), 3.75 and 3.80 (2H, 2 x s, NCH2C02C), 3.93 (2H, q, J 7,
CH3CH2D2CCH2CH2) and 3.93 (2H, q, J 7, CH3CH202CCH2N), bc (100) 13.10
(CH3), 13.16 (CH3), 22.31 and 22.61 (CH2), 30.05 and 30.21 (CH2), 46.42 and 46.60
(CH2), 47.89 and 48.14 (CH2), 51.59 and 51.66 (CH3), 59.14 and 59.44 (CHV, 59.92
and 60.04 (CH2), 155.58 and 155.94 (C), 168.71 and 167.72 (C) and 171.90 (C), m/7
136
275 (3%, M), 230 (9, M-OEt), 216 (6, M-C02Me) 202 (2, M-C02Et), 188 (6, M
CH2C02Et), 128 (8, M-C02Et-OEt) and 70 (33, M-C02Et-C02Et-CChMe), [Found:
M, 275.1350. C12H21N06 requires M, 275.1369].
(±)-1-Methyl-4-ethyl 3-oxopiperidine-l,4-dicarboxylate (207)
(209) (207)
Potassium tert-butoxide (4 g, 36.4 mmol) was added in portions over 10min to a
solution of the N-protected diester (209) (10 g, 36.4 mmol) in dry toluene (150 ml).
After a further 30min the reaction mixture was acidified to pHI with 2M aqueous
hydrochloric acid, the organic layer separated and the aqueous phase further
extracted with dichloromethane (3 x 100 ml). The organic phases were combined,
washed with saturated aqueous sodium chloride (50 ml), dried and concentrated
in vacuo. Chromatography of the residue over silica gel eluting with
dichloromethane: ethyl acetate (9:1) gave the title compound (207) (4.25g, 51%) as
a colourless oil, RF 0.9, 'Umax 1668, 1701 and 3350cm-1, OH (400) 1.31 (3H, t, J 7,
CH3CH2ChC), 2.34 (2H, br s, NCH2CH2), 3.54 (2H, br s, NCH2CH2), 3.73 (3H, s,
CH3D2CN), 4.06 (2H, s, NCH2C=O), 4.23 (2H, q, J 7, CH3CH202C) and 12.01 (1H,
br s, OH), oe (100) 13.31 (CH3), 21.48 (CH2), 40.23 (CH2), 44.07 (CH2), 51.66 (CH3),
59.64 (CH2), 95.87 (C), 154.77 (C), 166.62 (C) and 170.85 (C), m/ z 229 (55%, M), 184
(16, M-EtO), 168 (9, M-Et02), 156 (36, M-C02Et), 140 (50, M-C02Et-0), 59 (67,
C02Me) and 45 (36, EtO), [Found: M, 229.0952. CloH1SNOS requires M, 229.0950].
137
.,'
(±)-1-tert-Butyl-3-ethyI4-oxopiperidine-1,3-dicarboxylate (135)
(134) (135)
Di-tert-butyl dicarbonate (5.8 g, 26.5 mmol) was added dropwise to a solution of
ethyl 4-oxopiperidine-3-carboxylate hydrochloride (134) (5 g, 24.1 mmol; Fluka)
and triethylamine (2.68 g, 26.5 mmol) in dichloromethane. (100 ml) The reaction
mixture was stirred overnight at room temperature, diluted with dichloromethane
(200 ml), washed with 2M aqueous hydrochloric acid (2 x 30 ml), and saturated
aqueous sodium chloride (30 ml), dried and concentrated in vacuo to give the title
compound (135) (5.1 g, 78%) as a colourless oil, "max 1665, 1698 and 3369 em-I,
OR (400, 333K) 1.31 (3H, t, J 7, CH3CH20), 1.48 (9H, s, (CH3hC), 2.37 (2H, br t, J 5.8,
NCH2CH2), 3.57 (2H, t, J 5.9, NCH2CH2), 4.06 (2H, s, NCH2C(C02Et)), 4.24 (2H, q,
J 7, CH3CH202C) and 12.07 (lH, s, OH), oe (68.5) 13.66 (CH3), 27.93 (CH3), 28.45
(CH2), 38.89 (CH2), 39.84 (CH2), 60.07 (CH2), 84.58 (C), 95.53 (C), 154.11 (C), 169.49
(C) and 169.85 (C), m/ z 214 (40%, M-(CH3hC), 198 (9, M-C02Et), 170 (10, M-BOC),
142 (12, M-(CH3hC-C02Et+H), 98 (28, M-BOC-C02Et+H) and 57 (100, (CH3hC),
[Found: M-(CH3hC, 214.0743. C9H12NOs requiresM-(CH3)3C, 214.0715].
(3R, 4S)-1-tert-Butyl-3-ethyl 4-hydroxypiperi dine-1,3-dicarboxylate (152)
(135)
138
OH
O,·,\C02EI
N I
BOC
(152)
.,'
The piperidine f3-keto-ester (135) (5 g, 18.5 nunol) was added to a fermenting
solution of dried baker's yeast (30 g) and sucrose (50 g) in tap water (500 ml).
Fermentation continued for 16h and the yeast residues were removed by filtration.
The filtrate was filtered 5 x through kieselguhr and extracted with
dichloromethane (5 x 200 ml). The combined organic extracts were washed with
saturated aqueous sodium chloride (l00 ml), dried and concentrated in vacuo to
give the title compound (152) (3.73 g, 74%) as an off white solid, m.p. 58-60°C,
[a]D23 +25.6 (c=3.4 in CH2C12), Umax 1668, 1732 and 3414cm-1, ~H (400, 333K) 1.21
(3H, t, J 7, CH3CH202C), 1.40 (9H, s, (CH3bCO), 1.55-1.62 (1H, m, NCH2CHAHB),
1.72-1.78 (lH, m, NCH2HAHB), 2.51 (2H, ddd, J 10.4,4.4 and 2.6, CHCOzEt), 3.19
(1H, ddd, J 14, 11 and 3, 6-Hax), 3.34 (lH, dd, J 14 and II, 2-Hax), 3.59 (1H, m,6-
Heq), 3.86 (lH, dd, J 14 and 4.1, 2-Heq), 4.12 (2H, q, J 7, CH3CH2C02C) and 4.20-
4.23 (lH, m, CHOH), ()c (68.5) 13.9 (CH3), 28.1 (CH3), 31.3 (CH2), 38.1 (CHz),40.3
(CH2), 45.6 (CH), 60.7 (CH2), 64.8 (CH), 79.5 (C), 154.5 (C) and 172.5 (C), mj z 273
(1%, M), 216 (13, M-(CH3bC), 200 (7, M-C02Et), 172 (11, M-BOC), 143 (4, M
(CH3bC-CH3CH2), 100 (14, M-BOC-C02Et+H), 82 (43, M-BOC-C02Et-OH), 73 (5,
Et02C) and 57 (100, (CH3bC), [Found: M, 273.1600. C13H2JNOs requires M,
273.1576].
(3S, 4S)-1-tert-Butyl 4-hydroxy3-hydroxymethylpiperidine-1-carboxylate (159)
OH
O""'-OH N I BOC
(152) (159)
The hydroxy ester (152) (2 g, 7.3 nunol) was added to a stirred ice-cooled
suspension of lithium aluminium hydride (1.1 g, 29.3 nunol) in tetrahydrofuran
139
(40 ml). After 3h 2M aqueous sodium hydroxide solution (1.1 ml) was introduced
and the reaction mixture filtered. The solid residue was washed with
dichloromethane (200 ml) and the combined organic filtrates washed with water
(20 ml), and saturated aqueous sodium chloride (20 ml), dried and concentrated in
vacuo to give the title compound (159) (1.22 g, 72%) as a thick colourless oil, [a ]D23
+ 14.0 (c=1.8 in CH2Ch), umax 1670 and 3420cm-1, ()H (400) 1.45 (9H, s, (ClIJhCO),
1.6-1.91 (3H, m, CHCH20H and NCH2CH2), 2.40-2.52 (2H, m, 2-Hax and 6-Hax)
and 3.7-4.18 (5H, m, 2-Heq, 6-Heq, CH20H and CHOH), ()c (68.5) 25.57 (CH2),
28.41 (CH3), 39.25 (CH2), 41.46 (CH2), 41.74 (CH), 67.40 (CH), 67.94 (CH2), 79.80
(C) and 155.31 (C), m/ z 158 (16%, M-(CH3hC), 113 (6, M-BOC-OH) and 57 (100,
(CHJhC), [Found: M-(CH3hC, 158.0770. C9H12N03 requires M-(CH3)3C,
158.0817].
(3S1 4S)-1-tert-Butyl 4-hydroxy-3-0-tert-butyldiphenylsilyloxymethyl
piperidine-i-carboxylate (160)
OH OH
O··""'-OH N , BOC
O· J\, ......
,. "OTBDPS
N I BOC
(159) (160)
tert-Buty1chlorodiphenylsilane (1.31 g, 4.76 mmol) was added to a stirred solution
of the piperidine diol (159) (1 g, 4.3 mmol), triethylamine (0.48 g, 4.8 mmol) and 4-
dimethylaminopyridine (26 mg, 0.33 mmol) in dichloromethane (100 ml) and the
reaction mixture stirred at room temperature for 16h. The reaction mixture was
diluted with dichloromethane (200 ml), washed with water (50 ml), and saturated
aqueous sodium chloride (50 ml), dried and concentrated ill vacuo.
Chromatography of the residue over silica gel eluting with dichloromethane :
140
ethyl acetate (9:1) gave the title compound (160) (1.60 g, 79%) as a colourless oil,
RF 0.7, [a]D2l +10.6 (c=2.0 in CH2Ch), 'Umax 1665 and 3422cm-1, l)H (270) 1.06 (9H,
s, (CH3hCSi), 1.43 (9H, s, (CH3hCO), 1.49-1.78 (3H, m, NCH2CH2 and
CHCH20TBDPS), 3.20-3.35 (2H, m, 2-Hax and 6-Hax), 3.75-3.92 (4H, m, 2-Heq, 6-
Heq and CH20TBDPS), 4.21 (lH, br s, CHOH), 7.26-7.67 (lOH, m, 2xQjHs), l)C
(68.5) 19.08 (C), 26.79 (CH3), 28.43 (CH3), 32.29 (CHV, 38.71 (CH2), 41.37 (CH2),
41.51 (CH2), 65.61 (CH2), 67.85 (CH), 79.41 (C), 127.89 (CH), 129 97 (CH), 132.54
(C), 135.60 (CH) and 154.98 (C), mj z 470 (45%, M+H), 396 (3, M-(CH3hC) and 312
(12, M-BOC-(CH3hC), [Found: M+H, 470.2801. C27H39N04Si requires M+H,
470.2727].
(3S)-1-tert-Butyl 3-0-tert-butyldiphenylsilyloxymethyl pi peri dine-I-carboxylate
(162)
OH
O"""OTBDPS N I
BOC
(160)
__ ~ O·····''-OTBDPS N I BOC
(162)
Pentafluorophenyl chlorothionoformate (1.24 g, 4.7 mmol) was added to a stirred
solution of the piperidine (160) (0.37 g, 0.79 mmol), pyridine (0.13 g, 1.6 mmol) and
N-hydroxysuccinimide (18 mg, 0.16 mmol) in benzene (20 ml). The reaction
mixture was refluxed for 5h, cooled and concentrated in vacuo. Chromatography of
the residue over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave
the thionocarbonate (161) (500mg, 91%) as a colourless oil. RF 0.85, l)H (270) 0.83
(9H, s, (CH3hCSi), 1.49-2.38 (3H, m, CHCH20TBDPS and NCH2CH2), 1.41 (9H, s,
(ClI3hCO), 2.55-3.23 (2H, m, 2-Hax and 6-Hax), 3.40-3.62 (2H, ffi, CH20TBDPS),
141
3.72-4.04 (2H, m, 2-Heq and 6-Heq), 5.64 ( 1H, br s, CHO(CS)OQjFs) and 7.24-7.65
(10H, m, 2xQjHs), which was used directly.
The thionocarbonate (500 mg, 0.72 mmol) was refluxed with tri-n-butyltin hydride
(0.21 g, 0.72 mmol) and azo-bis-iso-butyronitrile (6 mg, 0.04 mmol) in benzene (20
ml) for 30min. The reaction mixture was cooled and concentrated in vacuo.
Chromatography of the residue over silica gel eluting with dichloromethane :
ethyl acetate (9:1) gave the title compound (162) (280 mg, 58%) as a colourless oil,
RF 0.70, [a]D2S +12.6 (c=1.15 in CHClJ), '-'max 1665 em-I, OR (400) 1.0-1.3 (2H, m,
NCH2CH2CH2), 1.11 (9H, s, (CH3hSi), 1.45-1.60 (2H, m, NCH2CH2), 1.47 (9H, s,
(CItbCO), 1.75 (1H, m, CHCH20TBDPS), 2.5-2.62 (lH, m, 6-Hax), 2.62-2.75 (lH,
m, 2-Hax), 3.49-3.56 (2H, m, CH20TBDPS), 4.0 (1H, m, 6-Heq), 4.2 (lH, m, 2-Heq)
and 7.3-7.75 (10H, m, 2xC6HS), oe (100, 333K) 19.34 (C), 24.72 (CH2), 26.93 (CH3),
27.23 (CH2), 28.55 (CH), 38.74 (CH), 44.40 (CHV, 47.53 (CH2), 66.41 (CH2), 79.80
(C), 129.69 (CH), 133.71 (CH), 133.72 (C), 135.41 (CH) and 155.07 (C), rnj z454 (10%,
M+H), 396 (7, M-tBu), 352 (35, M-BOC), 199 (90, M-BOC-(2xPh)+H) and 198 (46,
M-BOC-(2xPh», [Found: M+H, 454.2778. C27H4oN03Si requires M+H, 454.2777].
(3S)-1-(p-Toluenesulphonyl) 3-0-tert-butyldiphenylsilyloxymethylpiperidine
(164)
O·· .. "'OfBDPS N I Boe
(162)
O""'OfBDPS N I
Ts
(164)
Trifluoroacetic acid (1.51 g, 13.25 mmol) was added to a stirred solution of the
piperidine (162) (200 mg, 0.44 mmol) in dichloromethane (20 ml). After 1h the
reaction mixture was diluted with dichloromethane (100 ml), washed with
saturated sodium hydrogen carbonate (2 x 20 ml), dried and concentrated in vacuo.
142
The residue was dissolved in dichloromethane (5 ml) and added to a stirred
solution of p-toluenesulphonyl chloride (168 mg, 0.88 mmol), triethylamine (178
mg, 1.77 mmol) and 4-dimethylaminopyridine (3 mg, 0.02 mmol) in
dichloromethane (5 ml). After 16h the reaction mixture was diluted with
dichloromethane (50 ml), washed with water (10 ml), saturated aqueous sodium
chloride (10 ml), dried and concentrated in vacuo. Chromatography of the residue
over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave the title
compound (164) (166 mg, 74%) as a colourless oil, RF 0.60, [a]D22 -22.3 (c=1.1 in
CHCIJ), 1Jmax 1114, 1361 and 1673cm1, ()H (270) 1.03 (9H, s, (CH3hCSi), 1.42-1.97
(4H, m, NCH2CH2CH2 and NCH2CH2), 2.12 (lH, app. t, J 10.5, 6-Hax), 2.26 (lH,
dt, J 11.7 and 3.5, 6-Hax), 2.43 s (3H, s, CH3C6H4), 3.41-3.78 (5H, m, 2-Heq, 6-Heq,
CHCH20TBDPS and CHCH20TBDPS) and 7.28-7.68 (14H, m, 2XC6Hs and
S02C6f4ClfJ), ()C (68.5) 14.02 (CH3), 19.23 (C), 24.12 (CHV, 25.59 (CHV, 26.34
(CH3), 38.15 (CH), 46.70 (CH2), 60.39 (CH2), 66.02 (CH2), 127.56 (CH), 129.40 (CH),
133.19 (C), 134.30 (CH), 134.98 (CH), 135.63 (CH), 143.29 (C) and 171,21 (C), m/ z
450 (1%, M-tBu), 199 (100, M-Ts-(2xPh)+H), 78 (7, C6H6) and 77 (12, C6Hs),
[Found: M-tBu, 450.1576. C2sH2SN03SSi requires M3Bu, 450.1550].
(3S)-1-(p-Toluenesulphonyl) 3-hydroxymethylpiperidine (165)
. -' OH 0 ··· ........... I
Ts
(164) (165)
Tetrabutylammonium fluoride (0.397 mI, 1M in tetrahydrofuran, 0.4 mmol) was
added to a stirred solution of the piperidine (164) (100 mg, 0.2 mmol) in
tetrahydrofuran (0.5 ml). The reaction mixture was stirred for 16h at room
temperature, diluted with dichloromethane (100 ml), washed with water (10 ml),
143
and saturated aqueous sodium chloride (10 ml), dried and concentrated in vacuo to
give the title compound (165) (53 mg, 78%) as a colourless oil, [a]D21 -16.52 (c=3.0
in CHCh), 'Umax 1149, 1379 and 3304cm-1, OH (270) 0.99-1.10 (1H, m,
NCH2CH2CHAHB), 1.50-1.97 (3H, m, NCH2CH2CHAHB and NCH2CH2), 2.24
(lH, br t, 6-Hax), 2.44 (3H, s, CH3C61f4), 2.29-2.53 (lH, m, 2-Hax), 3.18-3.71 (5H, m,
2-Heq, 6-Heq, CHCH20H and CH20H), 7.30 (2H, d, J 8.3, CH(fosyl» and 7.62
(2H, m, CH(Tosyl», Oc (68.5) 21.42 (CH3), 23.85 (CH2), 26.06 (CH2), 38.01 (CH),
46.52 (CH2), 48.97 (CH2), 64.67 (CH2), 127.57 (CH), 129.54 (CH), 132.96 (C) and
143.38 (C), m/ z 269 (1%, M), 238 (1, M-CH20H), 156 (2, CH3C61f4S02H), 115 (8, M
Ts+H), 114 (100, M-Ts), 91 (69, CH3C6Hi), 84 (7, M-Ts-CH20H+H) and 83 (6, M
Ts-CH20H), [Found: M, 269.0972,.Cl3H19N03S requires M, 269.1086].
(3S)-N,O-di-(p-Toluenes ul phonyD-3-oxymethylpiperi dine (158)
0,·>', .- OH
N 0
,\1, .-- OTs
N I I
Ts Ts
(165) (158)
p-Toluenesulphonyl chloride (39 mg, 0.20 mmol) was added to a solution of the
piperidine (165) (50 mg, 0.19 mmol), triethylamine (21 mg, 0.20 mmol), and 4-
dimethylaminopyridine (0.01 mmol) in dichloromethane (10 ml). The reaction
mixture was stirred for 16h at room temperature, diluted with dichloromethane
(l00 ml), washed with water (5 ml), and saturated aqueous sodium chloride (5 ml),
dried and concentrated in vacuo. The residue was recrystallised from hot methanol
to give the title compound (158) (46 mg, 63%) as a white solid, mp 88-89° ,[ a)D25
-50.2 (c=1.1 in CHCb), [Lit m.p 87-89° , [a)D25 +54 for the R-enantiomer),115 'Umax
1175, 1342 and 1359cm-1, OH (400) 1.03-1.11 (lH, m, NCH2CH2CHAHB), 1.49-1.65
(3H, m, NCH2CH2CHAHB and NCH2CH2), 1.93-1.97 (1H, m, CHCH20Ts), 2.27
144
(1H, t, J 9.5, 6-Hax), 2.38 (3H, s, CH3C6HiS02N), 2.41 (3H, s, CH3e6t4S020), 2.48-
2.55 (lH, m, 2-Hax), 3.39-3.47 (2H, m, 2-Heq and 6-Heq), 3.83 (lH, dd, J 10 and 6.6,
CHAHBOTs), 3.91 (lH, dd, J 10 and 6, CHAHBOTs), 7.25 (lli, d, J 8.3, eH(N
Tosyl», 7.30 (2H, d, J 8.3, CH(O-Tosyl), 7.55 (2H, d, J 8.3, eH(N-Tosyl) and 7.72
(2H, d, J 8.3, CH(O-Tosyl», {)c (100) 21.51 (CH3), 21.65 (CH3), 23.49 (eH2), 25.68
(eH2), 35.10 (CH), 46.64 (CH2), 48.29 (CH2), 71.39 (eH2), 127.62 (eH), 127.89 (eH),
129.04 (eH), 129.67 (CH), 132.56 (CH), 132.56 (e), 132.87 (e), 143.63 (e) and 145.01
(e), mj z 269 (4%, M-Ts+H), 268 (27, M-Ts), 252 (4, M-OTs), 156 (2, TsOH), 113 (3,
M-2xTs), 97 (7, M-Ts-OTs) and 91 (50, e6HSeH2), [Found: M-Ts+H, 269.1059.
Cl3HlsNOJ5 requires M-Ts+H, 269.1086].
(±)O,N-di-(p-Toluenesulphonyl)-3-oxymethylpiperidine (158)
(j0H N I
H
(166) (158)
p-Toluenesulphonyl chloride (780 mg, 4.0 mmol) was added to a solution of 3-
piperidinemethanol (166) (440 mg, 3.8 mmol), triethylamine (420 mg, 4.0 mmol),
and 4-dimethylaminopyridine (0.2 mmol) in dichloromethane (l00 ml). The
reaction mixture was stirred for 16h at room temperature, diluted with
dichloromethane (100 ml), washed with water (25 ml), and saturated aqueous
sodium chloride (25 ml), dried and concentrated in vacuo. The residue was
recrystallised from hot methanol to give the title compound (158) (730 mg, 50%) as
a white solid, mp 87-89° [Lit 87-89° for the R-enantiomer];llS all spectroscopic data
was consistent with the chiral material.
145
(2R, 3S)-1-(ferf-Butyl)-2-methyI3-hydroxypiperidine-1,2-dicarboxylate (167)
O,.··\OH
-III,
N C02Me I
BOC
(148) (167)
The piperidine f3-keto-ester (5g, 18.5mmol) was reacted with a solution of dried
baker's yeast by the method outlined for (3R, 4S)-1-tert-butyl-3-ethyl 4-
hydroxypiperidine-1,3-dicarboxylate (152) to give the title compound (167) (4.00
g, 80%) as a pale oil, [a]D22 +47.9 (c=3.8 in CH2Clz), umax 1695, 1739 and 3437 cm-
1, bH (400) 1.41-1.59 (lH, m, CHAHBCHOH), 1.43 (9H, s, (CH3hCO), 1.67-1.78 (lH,
m, CHAHBCHOH), 1.91-2.00 (2H, m, NCH2CH2), 2.79 (lH, hr s, 6-Hax), 3.70-3.82
(lH, m, CHOH), 3.74 (3H, s, CH3C02C), 3.92 OH, br d, J 13.3, 6-Heq) and 4.54 (lH,
br s, 2-Heq), be (l00) 23.40 and 24.00 (CH2), 28.28 (CH3), 30.08 (CH2), 40.00 and
41.40 (CH2), 52.26 (CH3), 57.30 and 58.90 (CH), 68.91 (CH), 80.62 (C), 154.90 (C)
and 172.41 (C), mj z 200 (6%, M-C02Me), 158 02, M-BOC), 127 (2, M-BOC-OMe),
100 (91, M-BOC-C02Me+H), 59 (2, C02Me) and 57 (100, (CH3hC), [Found: M
C02Me, 200.1289. CloH18N03 requires M-C02Me, 200.1287].
(2S, 3S)-1-ferf-ButyI3-hydroxy-2-hydroxymethylpiperidine-1-carboxylate (170)
O,.\OH
::. /OH "I
N I BOC
(167) (170)
The hydroxy ester (167) (2 g, 7.7 mmol) was added to a stirred ice-cooled
suspension of lithium aluminium hydride (1.17 g, 30.9 mmol) in tetrahydrofuran
(50 ml). After 3h 2M aqueous sodium hydroxide solution (1.2 ml) was introduced
146
and the reaction mixture filtered. The solid residue was washed with
dichloromethane (200 ml) and the combined organic filtrates washed with water
(20 ml), and saturated aqueous sodium chloride (20 ml), dried and concentrated in
vacuo to give the title compound (170) (1.28 g, 72%) as a colourless oil, [a]D22 + 19.5
(c=1.6 in CH2Ch), Vmax 1678 and 3425cm-1, ~H (400, 333K) 1.39 (9H, s,
(CH3hCO), 1.42-1.78 (4H, m), 2.81 (1H, app br t, J 13.5, 6-Hax), 3.68-3.72 (1H, m, 6-
Heq), 3.7 (lH, dd, J 11.3 and 6.5, CHAHBOH), 3.87 (lH, dt, J 10.3 and 4.9, CHOH),
4.03 (1H, dd, J 11.3 and 6.4, CHAHBOH) and 4.25 (lH, dt, J 5.7 and 6.1, 2-Heq), ~c
(68.5) 23.74 (CH2), 28.36 (CH2), 28.41 (CH3), 39.70 (CH2), 55.97 (CH), 59.37 (CH2),
69.47 (CH), 80.34 (C) and 155.68 (C), mj z 158 (12%, M-(CH3hCO) and 57 (95,
(CH3hC), [Found: M-(CH3hCO, 158.0808. C7H12N03 requires M-(CH3hCO,
158.0817].
(2S, 3S)-1-tert-Butyl 3-hydroxy-2-0-tert-butyldiphenylsilyloxymethyl
pi peri dine-i-carboxylate (171)
O,,·'OH
'_, ........ OH N I,;"
I BOC
(170)
O··'OH
':.. ....OTBDPS N I,;"
I BOC
(171)
tert-Buty1chlorodiphenylsilane (1.31 g, 4.76 mmol) was added to a stirred solution
of the piperidine diol (170) (1 g, 4.3 mmol), triethylamine (0.48 g, 4.8 mmol) and 4-
dimethylaminopyridine (26 mg, 0.33 mmol) in dichloromethane (100 ml) and the
reaction mixture stirred at room temperature for 16h. The reaction mixture was
diluted with dichloromethane (200 ml), washed with water (50 ml), and saturated
aqueous sodium chloride (50 ml), dried and concentrated ill vaCllO.
Chromatography of the residue over silica gel eluting with dichloromethane :
ethyl acetate (9:1) gave the title compound (171) (1.59 g, 78%) as a colourless oil,
147
Rp 0.65, [a]D22 +42.8 (c=3.5 in CH2Cb), Umax 1668 and 3424cm-1, bH (400, 333K)
1.09 (9H, s, (CH3hCSi), 1.44 (9H, s, (CIthCO), 1.47-1.65 (3H, m), 1.88 (lH, br d, J
9.2, NCH2CHAHB), 2.64 (lH, br t, J 13.3, 6-Hax), 2.89 (lH, br s, OH), 3.84-3.90 (3H,
m, 6-Heq, CHOH, CHAHBOTBDPS), 4.10 (lH, dd, J 10.4 and 7.2,
CHAHBOTBDPS), 4.58 (lH, dt, J 6.3 and 6.2, 2-Heq) and 7.38-7.72 (lOH, 2m,
2XC6Hs), be (100) 19.11 (C), 23.99 (CH2), 26.83 (CH3), 28.42 (CH3), 28.94 (CH2),
38.88 (CH2), 54.91 (CH), 60.72 (CH2), 69.92 (CH), 79.11 (C), 127.88 (CH), 129.94
(CH), 132.81 (C), 135.65 (CH) and 154.85 (C), mj z 396 (3%, M-(CH3hCO), 143 (4,
M-OTBDPS-BOC), 100 (l00, M-CH2OTBDPS-BOC+H) and 57 (45, (CH3hC),
[Found: M-(CH3hCO, 396.1897. C23H30N03Si requires M-(CH3hCO, 396.1995].
(2R)-1-ferf-Butyl 2-0-ferf-butyldiphenylsilyloxymethylpiperidine-l-carboxylate
(173)
O.l,'OH
-.. OTBDPS N 1,/ I Boe
(171)
0 .. -.... arBDPS N 1,/
I Boe
(173)
1,1'-Thiocarbonyl diimidazole (380 mg, 2.1 mmol) was added to a stirred solution
of the piperidine (171) (0.5 g, 1.1 mmol) in dichloromethane (20 ml). The reaction
mixture was refluxed for 24h, cooled and concentrated in vacuo. Chromatography
of the residue over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave
the thionourethane (172) (570mg, 95%) as a colourless oil, RF 0.3, bH (270) 1.02
(9H, s, (CH3hCSi), 1.48 (9H, s, (CH3hCO), 1.62-2.05 (4H, m), 3.00 (lH, br t, J 13.5,
6-Hax), 3.80-4.05 (3H, m, CH20TBDPS and 6-Heq), 4.75-4.82 (lH, fi, 2-Heq), 5.53
(lH, ddd, J 12, 6 and 6, CHO(CS)Im), 7.01 (lH, br s, NCH=CHN), 7.26-7.66 (11H,
m, 2xC6Hs and NCH=CHN) and 8.23 (lH, br s, NCH=N), be (68.5) 18.99 (C), 23.67
(CH2), 25.14 (CH2), 26.72 (CH3), 28.41 (CH3), 39.00 (CH2), 60.10 (CH), 60.14 (CH2),
148
79.59 (CH), 80.27 (C), 117.90 (C), 127.78 (CH), 127.89 (CH), 129.88 (CH), 129.94
(CH), 132.90 (C), 135.52 (CH), 135.60 (CH) and 154.70 (C).
The thiourethane (172) (570 mg, 1 mmol) was refluxed with tri-Il-butyltin hydride
(0.29 g, 1 mmol) and azo-bis-iso-butyronitrile (6 mg, 0.04 mmol) in toluene (10 ml)
for 2h. The reaction mixture was cooled and concentrated in vacuo.
Chromatography of the residue over silica gel eluting with dichloromethane :
ethyl acetate (9:1) gave the title compound (173) (243 mg, 53%) as a colourless oil,
Rp 0.60, [aJo21 +21.7 (c=1.4 in CH2Ch), 'Umax 1693 cm-1, ~H (270) 0.91 (9H, s,
(CIthCSi), 1.22-2.01 (6H, m), 1.29 (9H, Sf (CH3hCO), 2.61 (1H, br t, J 13.5, 6-Heq),
3.68 (2H, d, J 10.5, CH20TBDPS), 3.95 (1H, br d, J 13.5, 6-Heq), 4.36 (lH, br s, 2-
Heq) and 7.18-7.60 (10H, 2m, 2xC6HS), ~c (68.5) 19.07 (CH2), 19.12 (C), 24.78
(CHz), 25.28 (CH2), 26.78 (CBJ), 28.41 (CH3), 39.84 (CH2), 51.61 (CH), 61.48 (CH2),
79.08 (C), 127.64 (CH), 129.60 (CH), 133.55 (C), 135.63 (CH) and 155.08 (C), mj z 454
(4%, M+H), 397 (21, M-tBu+H), 352 (12, M-BOC) and 199 (100, M-BOC-(2xPh)+H),
[Found: M+H, 454.2777. C27H40N03Si requires M+H, 454.2777].
(2R)-1-(p-Toluenesulphonyl) 2-0-tert-butyldiphenylsilyloxymethylpiperidine
(175)
0 .. - OTBDPS N ',./ I
BOC
().. .,OTBDPS '.'/ N
I Ts
(173) (175)
TrifIuoroacetic acid (1.9 g, 16.6 mmol) was added to a stirred solution of the
piperidine (175) (250 mg, 0.55 mmol) in dichloromethane (20 ml). After 1h the
reaction mixture was diluted with dichloromethane (100 ml), washed with
saturated sodium hydrogen carbonate (2 x 20 ml), dried and concentrated ill vaCllO.
The residue was dissolved in dichloromethane (5 ml) and added to a stirred
149
solution of p-toluenesulphonyl chloride (210 mg, 1.1 mmol), triethylamine (223
mg, 2.2 mmol) and 4-dimethylaminopyrldine (3.4 mg, 0.03 mmol) in
dichloromethane (5 ml). After 16h, the reaction mixture was diluted with
dichloromethane (50 ml), washed with water (10 ml), saturated aqueous sodium
chloride (10 ml), dried and concentrated in vacuo. Chromatography of the residue
over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave the title
compound (175) (196 mg, 70%) as a colourless oil, RF 0.45, [a]D22 -20.1 (c=l in
CH2Ch), Vmax 1112, 1161 and 1343 cm-I, OH (270) 0.97 (9H, s, (CH3hCSi), 1.16-1.48
(5H, m), 1.90 (1H, br d, J II, NCH2CHAHB), 2.30 (3H, s, CH3C6Hi), 2.76 (lH, br t, J
11.4, 6-Hax), 3.53-3.72 (3H, m, CH20TBDPS and 6-Heq), 4.09-4.20 (1H, m,2-Heq),
7.13 (lH, d, J 8.2, CH (rosyl» and 7.28-7.64 (12H, m, 2xC6Hs and CH (Tosyl), Oc
(68.5) 18.31 (CH), 19.12 (C), 21.17 (CH2), 21.44 (CH3), 24.42 (CH2), 26.78 (CH3),
41.75 (CH2), 53.37 (CH), 61.12 (CH2), 126.81 (CH), 127.67 (CH), 129.52 (CH), 129.69
(CH), 133.32 (C), 135.54 (CH), 138.58 (C) and 142.66 (C), mj z 450 (69%, M
(CH3hC), 239 (14, M-CH20TBDPS+H), 238 (100, M-CH20TBDPS) and 155 (13,
CH3C6HiS02), [Found: M-(CH3hC, 450.1557. C2sH28N03SiS requires M-(CI!3J3C,
450.1559].
(2R)-1-(p-Toluenesulphonyl) 2-hydroxymethylpiperidine (176)
0., OTBDPS N 1,/ I
Ts
(175)
0 .. ~OH N -," I
Ts
(176)
Tetrabutylammonium fluoride (0.59 ml, 1M in tetrahydrofuran, 0.6 mmol) was
added to a stirred solution of the piperidine (175) (150 mg, 0.2 mmol) in
tetrahydrofuran (0.5 ml). The reaction mixture was stirred for 16h at room
temperature, diluted with dichloromethane (100 ml), washed with water (10 ml),
150
and saturated aqueous sodium chloride (10 ml), dried and concentrated in vacuo to
give the title compound (176) (54 mg, 68%) as a colourless oil, [a]D23 +17.3 (c=1.5
in CH2Ch), 'Umax 1115, 1184 and 1354 em-I, bH (400) 1.00-1.38 (5H, m), 1.52 (lH, d,
J 13.5, NCH2CHAHB), 2.24 (3H, s, CH3C6H4), 2.90 (1H, br t, J 11.4, 6-Hax), 3.46
(1H, dd, J 11.2 and 7, 6-Heq), 3.61 (2H, dd, J 11.2 and 7.6, CH20H), 3.87-3.95 (1H,
m, 2-Heq), 7.13 (1H, d, J 8.2, CH (fosyl) and 7.59 (1H, d, J 8.2, CH (fosyl), be (100)
18.41 (CH2), 20.98 (CH3), 23.61 (CH2), 23.98 (CH2), 41.02 (CH2), 53.91 (CH), 59.83
(CH2), 128.54 (CH), 129.32 (CH), 137.99 (C) and 142.89 (C), mj z 238 (100%, M
CH20H), 84 (12, M-CH20H-CH3C6H4S02+H), 83 (8, M-CH20H-CH3C6l-4S02),
[Found: M-CH20H, 238.0863. CI2HI6N02S requires M-CH20H, 238.0902].
(2R)~N,O, -di~(p-Toluenesulphonyl) 2-hydroxymethylpiperidine (169)
0 .- OH N "'/ Q ...... /OTS
I I Ts Ts
(176) (169)
p-Toluenesulphonyl chloride (39 mg, 0.20 mmol) was added to a solution of the
piperidine (176) (50 mg, 0.19 mmol), triethylamine (21 mg, 0.20 mmol), and 4-
dimethylaminopyridine (0.01 mmol) in dichloromethane (10 ml). The reaction
mixture was stirred for 16h at room temperature, diluted with dichloromethane
(100 ml), washed with water (5 ml), and saturated aqueous sodium chloride (5 ml),
dried and concentrated in vacuo. Chromatography of the residue over silica gel
eluting with dichloromethane : ethyl acetate (9:1) gave the title compound (169)
(55 mg, 75%) as a colourless oil, RF 0.40, [a]D23 +55.0 (c=0.8 in CH2Ch), [Lit +56.6
for the (R)-enantiomer],128 'Umax 1160, 1177, 1190 and 1362cm-l, bH (400) 1.20-1.53
(SH, m), 1.68 (1H, br d, J 12.4, NCH2CHAHB), 2.40 (3H, s, CH3C6l-4S020), 2.44
(3H, s, CH3C6H4S02N), 2.81 (lH, br t, J 12.2, 6-Hax), 3.69 (lH, br d, J 12.2, 6-Heq),
151
4.01-4.12 (2H, m, eH20TS), 4.18-4.29 (lH, m, 2-Heq), 7.26 (2H, d, J 8.2, eH (N
rosyl», 7.4 (2H, d, J 8.2, eH (O-Tosyl», 7.66 (2H, d, J 8.2, eH (N-Tosyl» and 7.73
(2H, d, J 8.2, eH (O-Tosyl», be (l00) 18.20 (eH2), 21.38 (eH3), 21.54 (eH3), 23.99
(CH2), 24.29 (eH2), 41.26 (eH2), 50.37 (eH), 66.78 (eH2), 126.65 (eH), 127.80 (eH),
129.65 (eH), 129.86 (eH), 132.42 (e), 137.74 (e), 143.22 (e) and 145.00 (e), rnj z 238
(100%, M-eH20S02e614Me) and 91 (43, eHJe6f4), [Found: M-eH2OS02
C6HtMe, 238.0889. e12H16N02S requires M-CH20S02C6I4Cll3, 238.0902].
(±)N,O-di-(p-Toluenes ul phonyl) 2-oxymethylpiperidine (169)
(177)
QOTS N I
Ts
(169)
p-Toluenesulphonyl chloride (1.17 g, 6.0 mmol) was added to a solution of 3-
piperidinemethanol (166) (660 mg, 5.7 mmol), triethylamine (630 mg, 6.0 mmol),
and 4-dimethylaminopyridine (0.3 mmol) in dichloromethane (100 ml). The
reaction mixture was stirred for 16h at room temperature, diluted with
dichloromethane (100 ml), washed with water (25 ml), and saturated aqueous
sodium chloride (25 ml), dried and concentrated in vacuo. to give the title
compound (169) (1.5 g, 70%) as a colourless oil; all spectroscopic data displayed
was consistent with the chiral material.
152
(3R, 4R)-1-Methyl-4-ethyI3-hydroxypiperidine-1,4-dicarboxylate (210)
&0 ~ &OH
N N I I e02Me e02Me
(207) (210)
The piperidine (3-keto-ester (207) (5 g, 21.8 mmol) was reacted with a solution of
dried baker's yeast by the method outlined for (3R, 4S)-1-tert-butyl-3-ethyl 4-
hydroxypiperidine-1,3-dicarboxylate (152) to give the title compound (210) (4.49
g, 89%) as a pale oil, [a]D21-21.4 (e=1.10 in CHCl), Vmax 1690, 1732 and 3460 eml,
bH (400) 1.28 (3H, t, J 7.1, CH3CH2C02C), 1.76 (lH, br d, J 13.5, NCH2CHAHB),
2.07 (1H, ddd, J 13.5, 10.6 and 4.4, NCH2CHAHB), 2.56 (1H, ddd, J 10.6, 4.7 and 2.4,
CHCDlEt), 2.87 (lH, br t, J 13.5, 6-Hax), 3.00 (lH, br d, J 13, 2-Hax), 3.70 (3H, s,
CH3C02C) 4.10-4.20 (3H, m, 2-Heq, 6-Heq and CHOH) and 4.21 (2H, q, J 7.1,
CH3CH2C02C), be (68.5) 13.96 (CH3), 22.18 (CH2), 42.88 (CH2), 45.07 (CH), 48.93
(CHv, 52.58 (CH3), 60.74 (CH2), 64.93 (CH), 156.59 (C) and 171.03 (C), mj z 254
(15%, M+Na), 232 (100, M+H), 214 (14, M-OH), 200 (21, M-MeO), 172 (6, M
C02Me) and 186 (13, M-EtO), [Found: M+H, 232.1175. CloHlsNOs requires M+H,
232.1185].
(3R, 4S)-1-MethyI3-hydroxy-4-hydroxymethylpiperidine-1-carboxylate (214)
(210) (214)
153
Sodium borohydride (4.84 g, 130 mmol) was added in portions over 10min to a
solution of the hydroxy ester (210) (3 g, 13.0 mmol) in methanol (100 ml) at O°C.
After 16h the reaction mixture was concentrated in vacuo, dissolved in
dichloromethane (300 ml), washed with water (20 ml), and saturated aqueous
sodium chloride (20 ml), dried and concentrated in vacuo. Chromatography of the
residue over silica gel eluting with ethyl acetate gave the title compound (214)
(1.7 g, 68%) as a colourless oil, RF 0.2, 'Umax 1680 and 3430 em-I, OH (270) 1.18-1.85
(3H, m, NCH2CH2 and CHCH20H), 2.62-3.06 (2H, m, 2-Hax and 6-Hax), 3.55-3.84
(2H, m, CH20H), 3.61 (3H, s, CH3C02C) and 3.90-4.20 (3H, m, 2-Heq, 6-Heq and
eHOH),oe (68.5) 22.19 (CH2), 41.22 (CH), 43.67 (CH2), 50.08 (CH2), 52.62 (CH3),
64.40 (CHV, 66.13 (CH) and 156.93 (C), mj z 189 (10%, M), 141 (14, M-CH20H-OH),
130 (23, M-C02Me), 82 (7, M-C02Me-CH20H-OH) and 59 (20, C02Me), [Found:
M, 189.1045. CgHlSN04 requiresM, 189.1001].
(3R, 4S)-1-MethyI3-hydroxy-4-0-p-toluenesulphonyloxymethylpiperidine-1-
carboxylate (215)
(214) (215)
The piperidine diol (214) (1 g, 5.3 mmol) was dissolved in dichloromethane (25 ml)
and added to a stirred solution of p-toluenesulphonyl chloride (1.11 g, 5.8 mmol)
and triethylamine (590 mg, 5.8 mmol) in dichloromethane (25 ml). After 16h the
reaction mixture was diluted with dichloromethane (100 ml), washed with water
(10 ml), 2M hydrochloric acid (30 ml) and saturated aqueous sodium chloride
(10 ml), dried and concentrated in vacuo. Chromatography of the residue over
154
silica gel eluting with dichloromethane : ethyl acetate (1:1) gave the title
compound (215) (1.52 g, 84%) as a colourless oil, RF 0.60, lJmax 1160, 1190, 1678
and 3425 em-I, bH (400) 1.25-1.56 and 1.94-2.00 (3H, 2 x m, NCH2CH2 and
CHCH20Ts), 2.45 (3H, s, CH3C6Ht), 2.73 (1H, br t, J 11.8, 6-Hax), 2.87 (lH, br d, J
13.9, 2-Hax), 3.68 (3H, s, CH3C02C), 3.70-3.93 (2H, m, CH20TS), 4.07-4.19 (3H, ffi,
2-Heq, 6-Heq and CHOH), 7.35 (2H, d, J 8.2, CH (fosyl) and 7.79 (2H, d, J 8.2, CH
(Tosyl», be (68.5) 14.02 (CH3), 21.84 (CHv, 39.57 (CH2), 43.18 (CHv, 49.80 (CH2),
52.56 (CH3), 60.24 (CH), 71.16 (CH2), 127.71 (CH), 129.74 (CH), 132.58 (C), 144.74
(C) and 156.71 (C), mj z 188 (5%, M-S02C6HtCHJ), 172 (6, M-OS02C6B4CHJ), 155
(7, M-OS02C6HtCHJ-OH) and 82 (5, CsHgN), [Found: M-S02C6B4CH3, 188.0879.
CgHI4N04 requires M-S02C6H4CH3, 188.0923].
UR, 5S)-8-Aza-N-(methyloxycarbonyl)-2-oxabicyclo-[3.4.0]-nonan-3-one (216)
(215) (216)
The piperidine tosylate (215) (500 mg, 1.5 mol) was added to a stirred suspension
of sodium cyanide (179 mg, 3.6 mmol) in dimethyl sulphoxide (10 ml). The
reaction mixture was heated at 50°C for 6h, cooled and 12M hydrochloric acid (50
ml) was introduced. After 16h the reaction mixture was extracted with
dichloromethane (2 x 100 ml) and chloroform (50 ml). The combined organic
extracts were washed with water (20 ml) and saturated aqueous sodium chloride
(20 ml), dried and concentrated in vacuo. Chromatography of the residue over
silica gel eluting with dichloromethane : ethyl acetate (1:1) gave the title
ISS
compound (216) (255 mg, 88%) as a colourless oil, RF 0.50, [a]D23 -22.4 (c=1.13 in
CHCh), 1Jmax 1701 and 1780cm-1, bH (400) 1.27-1.55 (lH, fi, NCH2CHAHB), 1.69-
1.83 (1H, fi, NCH2CHAHB), 2.26 (1H, dd, J 17.8 and 2, CHAHBC=O), 2.44-2.58 OH,
ffi, NCH2CH2CH), 2.67 (1H, dd, J 17.8 and 7.6, CHAHBC=O), 2.76-3.05 (1H, fi,6-
Hax), 3.25 (1H, br d, J 13.5, 2-Hax), 3.65 (3H, s, CH3C02C), 4.0-4.15 (1H, m, 6-Heq),
4.20 (1H, br d, J13.5, 2-Heq) and 4.37 (1H, br s, CH-O), be (68.5) 26.53 (CH2), 30.14
(CH2), 33.23 (CH), 41.57 (CH2), 44.60 (CH2), 53.32 (CH3), 76.41 (CH), 156.60 (C)
and 176.80 (C), mj z 199 (42%, M), 168 (12, M-OMe), 140 (100, M-C02Me) and 59
(18, C02Me), [Found: M, 199.0840. C9Hl3N04 requires M, 199.0845].
UR, SS)-8-Aza-N-(ferf-butyloxycarbonyl)-2-oxabicyclo-[3.4.0]-3-nonanone (218)
(216) (218)
Iodotrimethylsilane (603 mg, 3 mmol) was added to a stirred solution of the
lactone (216) (300 mg, 1.5 mmol) in chloroform 05 ml). The reaction mixture was
heated at 50°C for 8h, methanol (50 ml) was introduced, heating continued for 1h
and the reaction mixture was then concentrated in vacuo. The residue was
dissolved in dichloromethane (20 ml), triethylamine (305 mg, 3 mmol) and di-tert
butyl dicarbonate (660 mg, 3 mmol) were added and the reaction mixture stirred
at rOOfi temperature for 16h, diluted with dichloromethane (200 ml), washed with
2M aqueous citric acid (2 x 30 ml), and saturated aqueous sodium chloride (30
ml), dried and concentrated in vacuo. Chromatography of the residue over silica
gel eluting with dichloromethane : ethyl acetate (1:1) gave the title compound
156
(218) (345 mg, 95%) as a colourless oil, RF 0.50, [a]D23 -19.7 (c=1.3 in CHCb), lJmax
1686 and 1776cm-1, bH (400) 1.33-1.49 (lH, m, NCH2CHAHB), 1.43 (9H, s,
(CH3hC), 1.68-1.85 (lH, fi, NCH2CHAHB), 2.27 (1H, br d, J 17.8, CHAHBC=O),
2.49-2.62 (lH, m, NCH2CH2CH), 2.70 (lH, dd, J 17.8 and 7.6, CHAHBC=O), 2.75-
3.10 (lH, m, 6-Hax), 3.25 (lH, br d, J 13.5, 2-Hax), 3.62-4.01 (1H, m, 6-Heq), 4.20
(lH, br d, J 13.5, 2-Heq) and 4.45 (lH, br s, CH-O).
(3R, 4S)-N-(tert-Butyloxycarbonyl)-3-hydroxy-4-piperidineethanol (219)
o
(218) (219)
OH
OH
Sodium borohydride (189 mg, 5 mmol) was added to a solution of the lactone (300
mg, 1.2 mmol) in ethanol (20 ml) at O°C and the reaction mixture allowed to warm
to room temperature. After 16h the suspension was concentrated in vacuo, the
residue dissolved in dichloromethane (100 ml) and the solution washed with
water (5 ml) and saturated aqueous sodium chloride (10 ml), dried and
concentrated in vacuo. Chromatography of the residue over silica gel eluting with
ethyl acetate gave the title compound (207 mg, 68%) as a colourless oil, RF 0.2,
lJmax 1666 and 3419 cm-1, bH (400) 1.41-1.92 (4H, m, NCH2CH2 and CH2CH20H),
1.45 (9H, s, (CH3hC), 2.42-2.9 (lH, m, 6-Hax), 2.78 (lH, m, CHCH2CH20H), 2.93
(lH, br d, J 13.5, 2-Hax), 3.62-3.90 (4H, m, 2-Heq, 6-Heq and GI20H) and 4.0-4.15
(lH, fi, CHOH) which was used directly without further purification.
157
(lR,SS)-8-Aza-N-(tert-butyloxycarbonyl)-2-oxabicyc1o-[3.4.01-nonane (220)
(219)
OH
OH
(220)
Methanesulphonyl chloride (51 mg, 0.45 romol) was added to a solution of the
piperidine diol (219) (100 mg, 0.4 romol) and triethylamine (45 mg, 0.45 romol) in
dichloromethane (10 ml) at O°C. The reaction mixture was strirred at this
temperature for 3h, diluted with dichloromethane (100 ml), washed with water (5
ml) and saturated aqueous sodium chloride (5 ml), dried and concentrated in
vacuo to give the title compound (220) (76.6mg, 71%) as a colourless oil, [a ]D25
+8.0 (c=O.5 in CHCh), 'Umax 1110 and 1662 em-I, bH (400) 1.46 (9H, s, (CH3bC),
1.58-1.87 (3H, m, NCH2CH2 and NCH2CH2CH), 1.95-2.36 (2H, m, CH2CH20), 2.82
(lH, br t, J 13.5, 6-Hax), 3.28 (lH, dd, J 13.5 and 3, 2-Hax) and 3.62-4.25 (5H, m, 2-
Heq, 6-Heq and CH2CH20CH), m/ z 228 (2%, M+H), 171 (13, M-tBu), 155 (3, M
tBuO) and 57 (100, tBu), [Found: M+H, 228.1600. CI2H22N03 requires M+H,
228.1600].
(3R, 4R)-1-tert-Butyl-3-hydroxy-4-methyl-piperidine-l,4-dicarboxylate (222)
5~ ~ c5~H
N N I I
BOC BOC
(149) (222)
The piperidine ~keto-ester (149) (5 g, 21.8 romol) was reacted with a solution of
dried baker's yeast by the method outlined for (3R, 4S)-1-tert-butyl-3-ethyl 4-
158
hydroxypiperidine-1,3-dicarboxylate (152) to give the title compound (222) (4.08
g, 81%) as a pale oil, [a]D25 -32.7 (c=1.0 in CHCI3), umax 1690, 1735 and 3450 em-I,
OH (270) 1.46 (9H, s, (CH3hCO), 1.73 (lH, dt, J 3.6 and 13.5, 5-HAHB), 2.07 (lH,
ddd, J 13.5, 11.5 and 7.3, 5-HAHB), 2.56 (lH, ddd, J 10.6, 3.0 and 3.0, 4-H), 2.83 (lH,
dt, J 11.9 and 3.6, 6-Hax), 2.97 (lH, br d, J 13.2, 2-Hax), 3.73 and 3.78 (3H, 2 s,
CH30 ) and 4.03-4.19 (3H, m, 2-Heq, 6-Heq and 3-H), ()C (68.5) 22.41 (CH), 28.32
(CH3), 42.80 (CH2), 45.21 (CH2), 48.93 (CH2), 51.84 (CH3), 65.24 (CH), 79.84 (C),
155.54 (C) and 171.97 (C), mj z 200 (7%, M-C02Me), 158 (16, M-BOC), 141 (8, M
BOC-OH), 101 ( 5, BOC), 82 (7, M-BOC-C02Me-OH), 59 (5, C02Me) and 57 (100,
tBu), [Found: M-C02Me, 200.1269. CloHlgN03 requires M-C02Me, 200.1287]'
(3R, 4R)-1-tert-Butyl-4-methyl 3-(methyloxymethyloxy)-1,4-pi peri dine
dicarboxylate (223)
&OMOM N I
BOC
(222) (223)
Chloromethyl methyl ether (6.22 g, 77.2 mmol) was added to an ice-cooled
solution of the piperidine (222) (4 g, 15.4 mmol) and diisopropylethylamine (5 g,
38.6 mmol) in dichloromethane (200 ml) and the reaction mixture allowed to warm
to room temperature. After 16h the resulting solution was diluted with
dichloromethane (l00 ml), washed with 2M hydrochloric acid (2 x 40ml), and
saturated aqueous sodium chloride (50 ml), dried and concentrated in vaCllO.
Chromatography of the residue over silica gel eluting with ethyl acetate :
dichloromethane (9:1) gave the title compound (223) (4.3 g, 92%) as a colourless
oil, RF 0.6, [a]D25 +23.4 (c=0.9 in CHCI3), Umax 1687 and 1734 em-I, OH (270) 1.46
159
(9H, s, (CH3bCO), 1.60-2.17 (2H, m, 5-H), 2.49-2.90 (3H, m, 2-Hax, 6-Hax and 4-H),
3.33 (3H, s, CH30CH20), 4.02-4.48 (3H, m, 2-Heq, 6-Heq and 3-H), 4.55 (1H, d, J 7,
OCHAHBO) and 4.76 (lH, d, J 7, OCHAHBO), be (68.5) 22.54 (CH2), 28.79 (CH3),
42.64 (CH2), 45.82 (CH), 46.06 (CHv, 52.13 (CH), 56.03 (CH3), 69.97 (CH), 80.02
(C), 95.19 (CH2), 155.40 (C) and 173.08 (C), mj z 244 (8%, M-C02Me), 202 (7, M
BOC), 183 (5, M-C02Me-OMOM), 143 (5, M-C02Me-BOC), 141 (8, M-BOC
OMOM), 82 (8, M-BOC-C02Me-OMOM), 59 (11, C02Me) and 57 (100, tBu),
[Found: M-BOC, 202.1051. C9HI6N04 requires M-BOC, 202.1079].
(3R, 4R)-1-(tert-Butyloxycarbonyl) 3-(methyloxymethyloxy)-4-piperidine
carboxylic acid (224)
6 0MOM
N I Boe
(223)
&OMOM
N I BOC
(224)
The piperidine (223) (1 g, 3.3 mmol) was added to a stirred solution of potassium
hydroxide (0.92 g, 16.5 mmol) in water (10 ml) and the reaction stirred for 16h. The
resulting soluton was washed with diethyl ether (2 ml), acidified to pH 2 with 2M
citric acid and extracted with chloroform (3 x 30 ml). The combined extracts were
dried and concentrated in vacuo to give the title compound (224) (935 mg, 98%) as
a thick colourless oil, Uffiax 1691 and 3275 em-I, bH (400) 1.45 (9H, s, (CH3bCO),
1.68-1.80 (lH, m, 5-HAHB), 1.99-2.12 (1H, m, 5-HAHB), 2.48-2.88 (3H, m, 2-Hax, 6-
Hax and 4-H), 3.36 (3H, s, CH30CH20), 3.92-4.49 (3H, m, 2-Heq, 6- Heq and 3-H),
4.61 (lH, d, J 7, OCHAHBO) and 4.78 (lH, d, J 7, OCHAHBO), be (68.5) 20.81
(CH2), 28.16 (CH3), 42.70 (CH2), 45.07 (CH), 46.20 (CH2), 55.47 (CH3), 69.00 (CH),
79.66 (C), 94.50 (CH2), 154.93 (C) and 176.93 (C), mj z 312 (35%, M+Na), 290 (66,
160
M+H), 258 (14, M-OMe), 232 (13, M-tBu), 188 (21, M-BOC) and 128 (33, M-BOC
OCH20CH3+H ), [Found: M+H, 290.1614. CIJH24N06 requiresM+H, 290.1604].
Ethyl-(3R, 4S)-N-(ferf-butyloxycarbonyl)-3-(methyloxymethyloxy)-4-piperidine
acetate (226)
&OMOM N I
BOC
(224)
OMOM
(226)
Freshly distilled oxalyl chloride (1.1 g, 8.6 mmol) was added to a stirred solution
of the piperidine carboxylic acid (224) (500 mg, 1.7 mmol) and dimethylformamide
(6.3 mg, 0.09 mmol) in diethyl ether (25 ml). The mixture was stirred at O°C for 30
mins and 90 mins at room temperature. The solvent and excess reagent were
evaporated in vacuo and the residue dissolved in diethyl ether (10 ml). An excess
of an ice cold ethereal solution of diazomethane was added, the solution left to
stand for 16h then concentrated in vacuo. Chromatography of the residue over
silica gel eluting with ethyl acetate: dichloromethane (9:1) gave the diazoketone
(225) (411 mg, 75%) as a colourless oil, RF 0.5, 'Umax 1686, 1734 and 2253 em-I, bH
(250) 1.35-1.72 (2H, m, 5-H), 1.45 (9H, s, (CH3bCO), 2.8-3.12 (3H, ffi, 2-Hax, 6-Hax
and 4-H), 3.40 (3H, s, CH)OCH20), 4.0-4.3 (3H, m, 2-Heq, 6-Heq and 3-H), 4.68
(1H, d, J 7, OCHAHBO), 4.72 (lH, d, J 7, OCHAHBO) and 5.31 (lH, s, HC=N2)·
Silver benzoate (14 mg, 0.06 mmol) and triethylamine (0.05 ml) were added to a
solution of the diazoketone (225) (411 mg, 1.2 mmol) in ethanol (15 ml) and the
reaction mixture stirred for 16h then concentrated in vacuo. Chromatography of
the residue over silica gel eluting with ethyl acetate: dichloromethane (9:1) gave
the title compound (226) (237 mg, 62%) as a colourless oil, RF 0.6, [(1]025 +18.0
161
(c=1.4 in CHCb), tlmax 1684 and 1740 em-I, ()H (400) 1.27 (3H, t, J 7, CH3CH20),
1.4-1.58 (1H, m,4-H), 1.45 (9H, s, (CH3hCO), 1.67-1.81 (1H, m, 5-HAHB), 2.03 (1H,
ddd, J 13.5, 11 and 7.3, 5-HAHB), 2.55 (lH, br d, J 11.9, 6-Hax), 3.28-3.40 (1H, m,2-
Hax), 3.55 (3H, s, CH30CH2), 4.1-4.4 (3H, m, 2-Heq, 6-Heq and 3-H), 4.17 (2H, q, J
7, OCH2CH3), 4.57 (1H, d, J 7, CHAHBO) and 4.75 (1H, d, J 7, CHAHBO), ()e (68.5)
13.95 (CBJ), 21.81 (CH2), 28.17 (CH), 40.03 (CHz), 45.50 (CH), 46.20 (CHv, 55.42
(CH3), 56.00 (CH2), 60.38 (CHz), 69.71 (CH), 79.46 (C), 94.59 (CHZ), 154.84 (C) and
172.01 (C), mj z 216 (10%, M-BOC), 143 (4, M-BOC-CHzCOzMe), 142 (7, M-BOC
COzMe-Me), 126 (40, M-BOC-CH2COzMe-Me), 82 (45, M-CH2C02Me-OCH20Me
BOC) and 57 (100, tsu), [Found: M-BOC, 216.1038. CIOHH~N04 requires M-BOC,
216.1236].
(3R, 4S)-1-tert-Butyl 3-(methyloxymethyloxy)-4-hydroxyethylpi peridine-l
carboxylate (227)
OMOM
(226) (227)
OH
OMOM
Diisobutylaluminuim hydride (1.7 mI, 2.52 mmol, l.5M in toluene) was added to a
solution of the piperidine (226) (200 mg, 0.63 mmol) in toluene (10 ml) at -78°C.
After 6h, saturated aqueous potassium tartrate (2 ml) was added, the suspension
diluted with dichloromethane (100 mI), washed with water (5 ml), and saturated
aqueous sodium chloride (10 mI), dried and concentrated in vacuo.
Chromatography of the residue over silica gel eluting with ethyl acetate:
dichloromethane (1:1) gave the title compound (227) (100 mg, 55%) as a colourless
oil, RF 0.6, tlmax 1688 and 3270 em-I, ()H (250) 1.27-1.52 (lH, m, 4-H), 1.42 (9H, s,
162
(CfI3bCO), 1.63 (2H, ddd, J 13.6, 11.2 and 7.3, 5-H), 1.70-1.90 (2H, m,
CH2CH20H), 2.60-2.85 (2H, m, 2-Hax and 6-Hax), 3.40 (3H, s, CH30CHV, 3.54-
3.71 (2H, m, CH20H), 3.89 (lH, br s, 6-Heq), 3.94-4.40 (2H, m, 2-Heq and 3-H),
4.61 (lH, d, J 7, OCHAHBO) and 4.80 (lH, d, J 7, OCHAHBO).
(3R, 4S)-1-tert-Butyl 3-(methyloxymethyloxy)-4-( O-methanesul phonyloxyethyl)
piperidine (228)
(227)
OH
OMOM
(228)
OMs
OMOM
Methanesulphonyl chloride (63 mg, 0.55 mmol) was added to a solution of the
piperidine (227) (80 mg, 0.28 mmol) and pyridine (44 mg, 0.55 mmol) in
dichloromethane (5 ml) at O°C. The reaction mixture was stirred at this
temperature for 3h, diluted with dichloromethane (100 ml), washed with water (5
ml) and saturated aqueous sodium chloride (5 ml), dried and concentrated in
vacuo to give the title compound (228) (63mg, 62%) as a colourless oil, lJmax 1690,
1112 and 1160cm-1, ()H (250) 1.36-1.78 (3H, m, 5-H and 4-H), 1.46 (9H, s,
(C~hCO), 1.98-2.16 (2H, m, CH2CH20Ms), 2.49-2.87 (2H, m, 2-Hax and 6-Hax),
3.01 (3H, s, CH3S02), 3.49 (3H, s, CH30CH2), 3.85 (lH, br s, 6-Heq), 4.03-4.51 (3H,
m, 2-Heq and CH20Ms), 4.57 (lH, d, J 7, OCHAHBO) and 4.80 (1H, d, J 7,
OCHAHBO).
163
(3R)-1-Aza-3-(methyloxymethyloxy)-b icyclo-[2. 2.2]-heptane (229)
I BOC
(228)
OMs
OMOM 7.~MOM Sr 4 3
6t-N 2
(229)
Trifluoroacetic acid (560 mg, 4.9 mmol) was added to a stirred solution of the
piperidine (228) (60 mg, 0.16 mmol) in dichloromethane (10 ml). After Ih the
reaction mixture was diluted with dichloromethane (100 ml), washed with
saturated sodium hydrogen carbonate (2 x 4 ml), dried and concentrated ill vacuo.
The residue was dissolved in ethanol (15 ml), refluxed for 6h and concentrated ill
vacuo. Chromatography of the residue over silica gel eluting with methanol :
ammonia (19:1) gave the title compound (229) (7.5 mg, 27%) as a colourless oil, RF
0.4, [a]D2S -23.4 (c=l in IN HCl), ~H (400) 1.86-1.97 (2H, m, 5-HAHB, 7-HAHB),
2.06-2.12 (1H, m, 5-HAHB), 2.19-2.25 (IH, m, 7-HAHB), 2.28-2.40 (1H, m, 4-H), 3.14
(lH, dt, J 13 and 3, 6-HAHB), 3.29-3.49 (4H, m, 2-HAHB, 6-HAHB and 8-H), 3.71
(lH, ddd, J 3, 8 and 13, 2-HAHB) and 4.24-4.26 (1H, m, CHOMOM), ~c (100) 18.25
(CH2), 21.91 (CH2), 28.52 (CH), 51.94 (CH2), 53.09 (CH2), 61.13 (CH), 61.57 (CH2),
65.03 (CHJ) and 92.76 (CH2).
3-(R)-1-Aza-3-hydroxy-bicyclo-[2.2.2]-heptane
[3-(R)-quinuclidinol] (151)
OMOM
CQ! (229)
164
(151)
12M hydrochloric acid (5 ml) was added to a solution of the quinuclidinol (229) (20
mg, 0.012 mmol) in ethanol (5 ml), the resulting solution was refluxed for 15 mins
and concentrated in vacuo. Chromatography of the residue over silica gel eluting
with methanol: ammonia (9:1) gave the title compound (151) (12 mg, 83%) as a
colourless oil, RF 0.15, [a]D25 -39.5 (c=O.5 in IN HCI), Lit [a]D20 +45.8° (c=3.0 in IN
HCl) for the (5) enantiomer,l33 Vmax 3450 cm-I, {)H (400) 1.12-1.47 (2H, m, 5-HAHB
and 7-HAHB), 1.48-1.78 (2H, m, 4-H and 5-HAHB), 1.79-2.00 (1H, m, 7-HAHB),
2.39-2.90 (5H, m, 2-HAHB, 8-H and 6-H), 2.91-3.09 (1H, ffi, 2-HAHB), 3.61-3.78 (1H,
m, 3-H) and 5.31 (lH, br s, OH), {)c (400) 18.67 (CH2), 28.53 (CH2), 28.12 (CH),
46.06 (CH2), 47.12 (CH2), 57.72 (CH2) and 66.72 (CH). This data is consistent with
an authentic sample of the racemic material from the Aldrich Chemical Company.
(±) 1-Benzyl-2-hydroxyethylpiperidine-1-carboxylate (298)
OH OH
(297) (298)
Benzyl chloroformate (13.2 g, 85.3 mmol) and 2M aqueous sodium hydroxide (40
mI, 85.3 mmol) were added simultaneously to a stirred solution of 2-
piperidine ethanol (297) (10 g, 77.5 mmol) and sodium hydroxide (3.1 g, 77.5 mmol)
in water (40 ml) at O°C. The reaction mixture was warmed to room temperature
and the resulting solution stirred for 16h, then acidified to pHI with 2M aqueous
hydrochloric acid and extracted with dichloromethane (3 x 150 ml). The combined
organic phases were washed with saturated aqueous sodium hydrogen carbonate
(50 ml) and saturated aqueous sodium chloride (50 ml), dried and concentrated ill
vacuo to give the title compound (298) (18.35 g, 90%) as a colourless oil, Umax
(CH2Ch) 1680 and 3220cm-l, {)H (270) 1.29-1.58 (7H, m, 3-CH2, -l-CH2,5-
165
CH2CHAHBCH20H), 1.81 (1H, app br t, J 13.3, CHAHBCH20H), 2.84 (1H, br t, J
13, 6-Hax), 3.39 ( 2H, m, CH20H), 3.91 (lH, hr d, J 13, 6-Heq), 4.34 (lH, m,2-Heq),
5.08 (2H, br s, PhCH2), 7.28-7.39 (5H, m, QjHs), ()e (100) 18.53 (CHv, 25.27 (CH2),
28.08 (CH2), 32.47 (CH2), 38.80 (CH2), 47.88 (CH), 58.32 (CH2), 66.02 (CH2), 127.32
(CH), 127.66 (CH), 128.34 (CH), 137.20 (C), and 154.65 (C), m/ z 264 (100%, M + H),
218 (2, M+ - CH2CH20H), 173 (2, M - C6HSCH2), and 156 (18, M - QjHs C H20),
[Found: M + H, 264.1600. ClSH21N03 requiresM+H, 264.1600].
(±) N-(Benzyloxycarbonyl)-2-piperidineethanal (299)
OH
(298) (299)
A solution of pyridine-sulphur trioxide complex (9.1 g, 19.0 mmol) in dimethyl
sulphoxide (29.6 mI, 380 mmol) was added to an ice-cooled solution of the
piperidine (298) (5 g, 19.0 mmol) and triethylamine (9.6 g, 95 mmol) in
dichloromethane (200 ml) under an atmosphere of nitrogen. The reaction mixture
was allowed to warm to room temperature and, after 16h, the resulting solution
was diluted with dichloromethane (200 mI), washed with water (3 x 30 mI) and
saturated aqueous sodium chloride (50 mI), dried and concentrated in vacuo.
Chromatography of the residue over silica gel eluting with dichloromethane :
ethyl acetate (9:1) gave the title compound (299) (4.0 g, 82%) as a colourless oil. RF
0.65, ()H (90) 1.3-2.15 (6H, m), 2.95 (lH, hr t, J 13, 6-Hax), 2.75 (2H, m, CH2CHO),
4.35 (1H, hr d, J 12, 6-Heq), 5.05 (1H, hr s, 2-Heq), 5.20 (2H, s, PhCHv, 7.42 (5H, s,
C6Hs) and 9.3 (lH, s, CHO) which was used directly without further purification.
166
Methyl 4-[ (±) N-(Benzyloxycarbonyl)-2-pi peri diny 1]-2-butenoate (301)
(299)
I Z
(301)
A solution of the aldehyde (299) (4.0 g, 15 mmol) and methyl triphenyl
phosphorylidene acetate (300) (5.6 g, 16.8 mmol) in dichloromethane (100 ml) were
stirred under a nitrogen atmosphere for 16h. The resulting solution was filtered,
the solid residue washed with dichloromethane (200 ml) and the combined
organic extracts concentrated in vacuo. Chromatography of the residue over silica
gel eluting with dichloromethane : ethyl acetate (9:1) to give the title compound
(301) (3.65 g, 75%) as a colourless oil, RF 0.6, "max 1685 and 1710 em-I, ()H (400)
1.18-1.30 (lH, m), 1.31-1.84 (5H, m), 2.21-2.27 (lH, m, CHAHBCH=CH), 2.32-2.38
(1H, m, CHAHBCH=CH), 2.64, (lH, br t, J 12.9, 6-Hax), 3.51 (3H, s, C02CH3), 3.95
(1H, br d, J 12.9, 6-Heq), 4.27 (lH, br s, 2-Heq), 4.92 (2H, s, PhCH2), 5.66 (lH, d, J
15.6, CH=CHC02Me), 6.69 (IH, dt, J 15.6 and 7.5, CH=CHC02Me) and 7.15 (5H, s,
C6HS), ()C (68) 18.35 (CH2), 24.71 (CH2), 27.39 (CH2), 32.20 (CH2), 38.64 (CH2),
49.36 (CH), 50.75 (CH3), 66.43 (CH2), 122.41 (CH), 127.22 (CH), 127.87 (CH), 127.49
(CH), 144.94 (CH), 154.73 (C) and 165.82 (C), mj z 335 (92%, M + Nl4) and 318
(100, M + H), [Found: M+H, 318.1704. ClsH24N04 requiresM+H, 318.1705].
167
4-[(±)-N-(Benzyloxycarbonyl)-2-piperidinyl]-2-buten-1-o1 (302)
OH
(301) (302)
A solution of diisobutylaluminium hydride (16.8 mI, 25 % wt soIn, 1.5 M, 25
mmol) was added to a solution of the piperidine (301) (2 g, 6.3 mmol) in toluene
(50 ml) at -78°C under an atmosphere of nitrogen. After 6h saturated aqueous
potassium tartrate was added (15 mI). The reaction mixture was warmed to room
temperature, filtered, and the residue washed with dichloromethane (200 mI). The
combined filtrates were washed with water (25 mI) and saturated aqueous sodium
chloride (25 mI), dried and concentrated in vacuo. Chromatography of the residue
over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave the title
compound (302) (1.6 g, 87%) as a colourless oil, RF 0.4, 'Umax 1680 and 3240 em-I,
{)H (250) 1.35-1.82 (6H, m), 2.19-2.34 (lH, m, CHAHBCH=CH), 2.39-2.65 (1H, m,
CHAHBCH=CH), 2.94, (1H, br t, J 13.5, 6-Hax), 3.19 (lH, br s, OH), 3.98-4.30 (3H,
m, CH20H, 6-Heq), 4.43 (1H, br s, 2-Heq), 5.19, (2H, s, PhCH2), 5.32-5.63, (2H, m,
CH=CH) and 7.43 (5H, s, C6HS), ()C (75) 18.74 (CH2), 25.37 (CH2), 27.81 (CH2),
32.79 (CH2), 39.23 (CH2), 50.52 (CH), 63.32 (CH2), 66.85 (CH2), 127.81 (CH), 127.90
(CH), 128.42 (CH), 128.98 (CH), 131.53 (CH) and 155.68 (C), mj z 290 (32%, M + H),
218 (24, M- CH2CH=CHCH20H), 92 (22, C6HsCH3), 91 (100, C6HSCH2) and 57 (3,
CH=CHCH20H), [Found: M+H, 290.1756. CI7H2JN03 requiresM+H, 290.1756].
168
4-[ (±)-N-(Benzyloxycarbonyl)-2-piperi dinyl]-( O-tert-butyl dimethylsil yl)-2-
buten-I-ol (303)
OH OTBDMS
(302) (303)
tert-Butyldimethylsilyl chloride (0.57 g, 3.8 mmol) was added to a solution of the
allylic alcohol (302) (1.0 g, 3.5 mmol), triethylamine (0.38 g, 3.8 mmol) and DMAP
(20 mg, 0.17 mmol) in dichloromethane (40 ml) under a nitrogen atmosphere. The
reaction mixture was stirred for 16 h, diluted with dichloromethane (100 ml),
washed with 2M aqueous citric acid (30 ml), water (10 ml) and saturated aqueous
sodium chloride (30 ml), dried and concentrated in vacuo. Chromatography of the
residue over silica gel eluting with dichloromethane : ethyl acetate (9:1) gave the
title compound (303) (1.10 g, 79%) as a colourless oil, RF 0.8, 'Umax 1690 em-I, ~H
(400) 0.01 (6H, s, Si(CH3h), 0.86 (9H, s, SiC(CH3h), 1.22-1.64 (6H, m), 2.21-2.27
(lH, m, CHAHBCH=CHCH20Si), 2.28-2.34 (lH, m, CHAHBCH=CHCH20Si), 2.80
(lH, br t, J 11, 6-Hax), 3.90-4.09 (lH, m, 6-Heq), 4.18-4.38, (lH, m, 2-Heq), 5.08 (2H,
s, PhCH2), 5.51-5.54 (2H, m, CH=CH) and 7.30 (5H, s, Q,Hs) , ~c (l00) -5.17 and
-5.30 (CH3), 18.29 (CH2), 18.91 and 18.70 (CH2), 22.53 (CH2), 25.58 and 25.41 (CHV,
25.93 (CH3), 32.66 (CHV, 39.25 and 39.04 (CHV, 50.75 and 50.34 (CH), 63.01 and
63.73 (CH), 66.79 (CH2), 127.25 (CH), 127.69 (CH), 127.77 (CH), 128.38 (CH) and
155.44 (C) , mj z 218 (28%, M-CH2CH=CHCH20TBDMS), 212 (7, M-PhCH2D2C -
tBu + H), 92 (20, Q;HsCH.3), 91 (l00, C6HsCH2) and 77 (3, Q,Hs), [Found: M
CH2CH=CHCH20TBDMS, 218.1214. C13H16N02 requires M-CH2CH=CHCH2-
OTBDMS, 218.1181].
169
4-[(±)-N-(Benzyloxycarbonyl)-2-piperidinyl]-(O-ferf-butyldimethyl-silyl)-2,3-
epoxy-butan-l-ol (304)
.... OTBDMS OTBDMS
(303) (304)
meta-Chloroperoxybenzoic acid (342 mg, 50% pure, 2 mmol) was added to a
stirred solution of the alkene (303) at room temperature. After 90min the reaction
mixture was diluted with dichloromethane (100 ml), washed with saturated
sodium hydrogen carbonate (30 ml) and saturated aqueous sodium chloride (30
ml), dried and concentrated in vacuo to give the title compound (304) (148 mg,
71%) as a colourless oil, RF 0.8, l)H (400) 0.04-0.09 (6H, m, Si(CH3h), 0.89 (9H, s,
C(CH3h), 1.12-1.75 (7H, m), 1.8-2.05 (lH, m), 2.65-2.9 (3H, m, 6-Hax and
CH2CH(O)GI), 3.48-3.58 (lH, m, CHAHBOTBDMS), 3.60-3.8 (1H, m,
CHAHBOTBDMS), 4.00 (lH, br s, 6-Heq), 4.55 (lH, br s, 2-Heq), 5.12-5.17 (2H, m,
PhCH2) and 7.27-7.36 (5H, m, C6Hs), l)C (68) -5.20 (CH3), 18.00 (CH2), 18.41 (C),
25.51 and 25.89 (CH2), 25.94 and 26.04 (CBJ), 28.32 (CH2), 32.27 and 32.88 (CH2),
39.19 and 39.48 (CHz), 48.88 and 49.08 (CH), 53.83 and 54.14 (CH), 58.61 (CH),
63.17 and 63.88 (CH2), 67.08 and 67.15 (CH2), 127.85 (CH), 127.97 (CH), 128.50
(CH), 137.00 (C) and 155.48 (C), m/ z 362 (5%, M-(CH3hC), 218 (7, M
CH2CHOCHCH20TBDMS), 108 (5, C6HsCH20H), 107 (5, C6HsCH20) and 91
(100, C6HsCH2), [Found: M-(CH3hC, 362.1803. C19H2gNO,pi requires M-(CH3)3C,
362.1788].
170
(±) N-(tert-ButyloxycarbonyD-2-piperidinemethanol (305)
QOH I
H
(177) (305)
Di-tert-butyl dicarbonate (4.18 g, 19.1 mmol) was added to a stirred solution of 2-
piperidinemethanol (177) (2 g, 17.4 mmol) and triethylamine (1.93 g, 19.1 mmol) in
dichloromethane (l00 ml). The reaction mixture was stirred for 16h, then acidified
to pHI with 2M aqueous citric acid and extracted with dichloromethane (3 x 150
ml). The combined organic phases were washed with saturated aqueous sodium
hydrogen carbonate (50 ml), saturated aqueous sodium chloride (50 ml), dried and
concentrated in vacuo to give the title compound (305) (3.0 g, 80%) as a colourless
oil, "max 1688 and 3430 cm-l, ()H (400) 1.34-1.68 (5H, m), 1.41 (9H, s, (CH3hCO),
1.74 (IH, ddd, J 13.1, 13.1 and 3.0, 5-HAHB), 3.57 (lH, ddd, J 13.1, 13.1 and 3.0, 6-
Hax), 3.71 (2H, dd, J 10.9 and 8.2, CH20H), 3.87 (lH, br d, J 13, 6-Heq) and 4.17-
4.21 (lH, m, 2-Heq). ()e (100) 19.61 (CH2), 25.23 (CH2), 28.44 (CH3), 28.70 (CH2),
40.18 (CH2), 52.80 (CH), 61.60 (CH2), 79.59 (C) and 156.08 (C), m/ z 238 (15%,
M+Na), 216 (65, M+H), 184 (53, M-CH20H), 158 (25, M-tBu), 142 (42, M-tsuO) and
114 (59, M-BOC), [Found: M+H, 216.1613. CllH22N03 requires M+H, 216.1600].
(±) N-(tert .. ButyloxycarbonyD-2-piperidinemethanal (306)
QOH N I
BOC
(305)
171
QO N I SOC
(306)
A solution of pyridine-sulphur trioxide complex (2.1 g, 13.1 mmol) in dimethyl
sulphoxide (7 ml, 96 mmol) was added to an ice-cooled solution of the piperidine
(305) (0.95 g, 4.4 mmol) and triethylamine (2.2 g, 21.8 mmol) in dichloromethane
(50 ml) . The reaction mixture was allowed to warm to room temperature and after
16h the resulting solution was diluted with dichloromethane (100 ml), washed
with water (3 x 20 ml) and saturated aqueous sodium chloride (20 ml), dried and
concentrated in vacuo. Chromatography of the residue over silica gel eluting with
dichloromethane: ethyl acetate (9:1) gave the title compound (306) (0.70 g, 74%) as
a colourless oil, RF 0.75, ()H (270) 1.15-1.63 (5H, m), 1.39 (9H, s, (CH3hCO), 1.92-2.1
(lH, m, 5-HAHB), 2.87 (lH, br t, J 12.4, 6-Hax), 3.84 (IH, br d, J 12.4, 6-Heq), 4.43-
4.55 (IH, m, 2-Heq) and 9.50 (lH, s, CHO), ()e (68.5) 20.41 (CH2), 23.11 (CH2), 24.26
(CHV, 27.72 (CH3), 42.12 (CH2), 60.71 (CH), 79.46 (C), 154.90 (C) and 199.84 (CH).
The sample was used directly.
l-tert-butyldimethylsilyloxy-2-propyne (307)
H _ , OH
---.... H- , OTBDMS
(307)
tert-Butyldimethylsilyl chloride (29.6 g, 196 mmol) was added to a stirred solution
of propargyl alcohol (10 g, 179 mmol), triethylamine (19.8 g, 196 mmol) and 4-
dimethylaminopyridine (1.1 g, 9 mmol) in dichloromethane (200 ml). The reaction
mixture was stirred for 16h, washed with 2M aqueous hydrochloric acid (2 x 40
ml) and brine (40 ml), dried and concentrated in vacuo. Chromatography of the
residue over silica gel eluting with dichloromethane : ethyl acetate (4:1) gave the
title compound (307) (24.9 g, 82%) as a colourless oil, RF 0.3, ()H (250) 0.05 (6H, S,
(CH3)Si), 0.88 (9H, s, (CH3hCSi), 2.36 (1H, s, C-H) and 4.27 (2H, S, CH2-0 ).
172
4-[(±)-N-(tert-Butyloxycarbonyl)-2-piperidinyl1-4-hydroxy_(O_tert-butyl
dimethylsilyD-2-butyn-l-ol (308)
OTBDMS
(306) (308)
Butyl lithium (1.46 mI, 1.6M in hexanes, 2.35 mmol) was added dropwise to a
solution of the alkyne (307) (439 mg, 2.58 mmol) in tetrahydrofuran (10 ml) at
-78°C. The reaction mixture was stirred at this temperature for 20min and at room
temperature for a further 20min. The resulting solution was cooled to -78°C and
the piperidine aldehyde (306) (500 mg, 2.35 mmol) was slowly added. Stirring
continued for 45min at this temperature and at room temperature for a further
45min. Saturated aqueous ammonium chloride (1 ml) was introduced, the reaction
mixture was diluted with dichloromethane (200 mI), washed with water (10 ml)
and saturated aqueous sodium chloride (10 ml), dried and concentrated in vacuo.
Chromatography of the residue over silica gel eluting with dichloromethane :
ethyl acetate (9:1) gave the title compound (308) (791 mg, 88%) as a colourless oil,
Rp 0.85, Umax 1687, 3240 em-I, l)H (400) 0.08 (6H, s, (CH3hSi), 0.88 (9H, s,
(CH.3hCSi), 1.14-1.67 (5H, m), 1.44 (9H, s, (CH3hCO), 1.94-1.99 (lH, ffi, 5-HAHB),
2.98 (lH, br t, J 11, 6-Hax), 3.92 (1H, br d, J 11, 6-Heq), 4.10-4.18 (1H, ffi, CHOH),
4.29 (2H, s, CH20Si) and 4.62 (1H, d, J 6.4, 2-Heq), l)C (100) -5.10 (CH:3), 18.29 (C),
19.47 (CH2), 24.41 (CH2), 24.66 (CH2), 25.87 (CH3), 28.54 (CH3), 40.81 (CH2), 51.84
(CH2), 55.93 (CH), 63.66 (CH), 79.77 (C), 84.17 (C), 84.70 (C) and 155.84 (C), mj z
406 (3%, M+Na), 384 (7, M+H), 326 (5, M-lBu), 310 (28, M-tBuO), 184 (20, M
CH(OH)C-CCH20TBDMS) and 128 (100, M-CH(OH)CCCH20TBDMS-tBu+H),
Found: M+H, 386.2716. C2oH4oNOpi requires M+H, 386.2727].
173
4-[ (±)-N-(tert-Butyloxycarbonyl)-2-pi peri dinyl]-4-hy droxy-( O-tert
butyldimethylsilyl)-2-buten-l-ol (309)
OTBDMS
OTBDMS
(308) (309)
The alkyne (308) (200 mg, 0.54 mmol) was added to a rapidly stirred solution of
palladium on barium sulphate (200 mg, 5%) and quinoline (30 J.lL) in ethyl acetate
(4 ml) under an atmosphere of hydrogen. The reaction mixture was stirred until
the requisite amount of hydrogen had been absorbed (ca O.5h), filtered through
kieselguhr and concentrated in vacuo to give the title compound (309) (185 mg,
92%) as a colourless oil, utnax1680 and 3254 em-I, ~H (400) 0.26 (6H, s, (CH3hSi),
0.86 (9H, s, (CH3bCSi), 1.22-1.62 (5H, m), 1.39 (9H, s, (CH3hCO), 2.03 (1H, br d, J
IS, 5-HAHB), 2.68 (lH, ddd, J 13, 13 and 3, 6-Hax), 4.00-4.07 (2H, m, CHOH and 6-
Heq), 4.19 (lH, ddd, J 13, 4.4 and 1.2, CHAHBOSi), 4.28 (1H, ddd, J 13,4.9 and 1.2,
CHAHBOSi) and 5.51-5.63 (2H, m, CH=CH), ~c (100) -5.1 (CH3), 18.13 (C), 19.40
(CH2), 24.29 (CH2), 25.07 (CH2), 25.81 (CH3), 28.36 (CH3), 40.44 (CH2), 55.20 (CHV,
59.63 (CH2), 65.87 (CH), 79.23 (C), 131.83 (CH), 132.14 (CH) and 155.12 (C), mj z
408 (3%, M+Na), 386 (20, M+H), 284 (15, M-BOC), 272 (9, M-TBDMS+H), 228 (10,
M-BOC-tBu+H), 184 (27, M-CH(OH)CH=CHCH20TBDMS) and 128 (100, M
CH(OH)CH=CHCH20TBDMS-tBu+H), [Found: M+H, 386.2716. C2olf4oN0 4Si
requires M+H, 386.2727).
174
4-[ (±)-N-(tert-Butyloxycarbonyl)-2-piperi dinyl]-4-acetoxy-( O-tert
butyldimethylsilyl)-2,3-epoxy-butan-l-01 (310)
OTBDMS OTBDMS
o
(309) (310)
m-Chloroperoxybenzoic acid (269 mg, 0.8 mmol, 50% pure) was added to a
solution of the alkene (309) (150 mg, 0.4 mmol) in dichloromethane (15 ml) at O°C.
The reaction mixture was warmed to room temperature, stirred for 90min, diluted
with dichloromethane (100 ml), washed with saturated aqueous sodium hydrogen
carbonate (5 ml), and saturated aqueous sodium chloride (5 ml), dried and
concentrated in vacuo to yield the epoxide. The crude epoxide was dissolved in
dichloromethane (20 ml), acetic anhydride (159 mg, 1.6 mmol) and pyridine (123
mg, 1.6 mmol) were added and the reaction mixture stirred at room temperature
for 16h. The resulting solution was diluted with dichloromethane (100 ml),
washed with 2M aqueous hydrochloric acid (2 x 7 ml), and saturated aqueous
sodium chloride (2 ml), dried and concentrated in vacuo. Chromatography of the
residue over alumina eluting with hexane : ethyl acetate (9:1) gave the title
compound (310) (124 mg, 72%) as a colourless oil, RF 0.90, ()H (400) 0.10 (6H, s,
(CH3hSi), 0.91 (9H, s, (CH3hCSi), 1.06-1.72 (6H, m), 1.46 (9H, s, (CH3hCO), 2.09
(3H, s, CH3CO), 2.74 (lH, br t, J 12.7, 6-Hax), 3.10 (1H, dt, J 4.2 and 6.3,
CHCH20Si), 3.17 (1H, dd, J 8.8 and 4,2, CHCHOAc), 3.72 (1H, dd, J 11.8 and 3.6,
CHAHBOSi), 3.91 (1H, dd, J 11.8 and 6.2, CHAHBOSi), 4.02 (lH, br d, J 12.7, 6-
Heq), 4.39-4.48 (1H, m, 2-Heq) and 5.19 (1H, dd, J 8.8 and 10, CHOAc), ()e (100)
-5.07 (CH3), 18.43 (C), 19.51 (CH2), 20.92 (CH3), 24.62 (CH2), 25.10 (CH2), 26.01
(CH3), 28.55 (CH3), 40.61 (CH2), 51.58 (CH2), 57.11 (CH), 58.60 (CH), 62.04 (CH2),
68.94 (CH), 80.09 (C), 154.84 (C) and 169.70 (C), m/ z 466 (1%, M+Na), 444 (2,
175
M+H), 443 (1, M), 386 (3, M-tBu) and 342 (12, M-BOC), [Found: M, 443.2698.
C22HUN06Si requires M, 443.2703].
1-Acetoxy-2-hydroxy-3-(hydroxymethyl)-indolizidine (312)
OTBDMS OAc
o
OAc
(310) (312)
Trifluoroacetic acid (455 mg, 0.14 mmol) was added to a stirred solution of the
piperidine (310) (60 mg, 0.14 mmol) in dichloromethane (20 ml). After 1h the
reaction mixture was diluted with dichloromethane (100 ml), washed with
saturated sodium hydrogen carbonate (2 x 20 ml), dried and concentrated in vacuo.
The residue was dissolved in methanol (20 ml), stirred at room temperature for
36h and concentrated in vacuo to give the title compound (312) (17 fig, 54%) as a
thick colourless oil, ()H (400) 1.25-1.35 (lH, m, 8-HAHB), 1.4-1.55 (2H, m, 6-CHAHB
and 7-HAHB), 1.65-1.74 (1H, m, 6-HAHB), 1.82-1.91 (lH, fi, 7-HAHB), 1.97 (1H, br
d, J 13, 8-HAHB), 2.12 (3H, s, CH3C02), 2.79 (lH, dt, J 3 and 13, 5-Hax), 2.97-3.38
(lH, m, 8a-H), 3.58-3.72 (3H, m, CHCH20H), 4.24 (lH, br d, J 13, 5-Heq), 4.31 (1H,
d, J 10, 2-H) and 5.15 (lH, dd, J 8 and 10, I-H), ()e (100) 20.48 (CH3), 24.05 (CH2),
25.97 (CH2), 31.88 (CHV, 46.28 (CH2), 59.62 (CH), 62.57 (CH2), 68.30 (CH), 67.00
(CH), 75.98 (CH) and 171.07 (C).
176
References
177
1 B. E. Rossiter and N. M. Swingle, Chern. Rev., 1992,92, 771.
2 R. O. Duthaler and A. Hafner, Chern. Rev., 1992, 92, 807.
3 K. Soai and S. Niwa, Chern. Rev., 1992, 92, 833.
4 For a review see S. Servi, Synthesis, 1990, 1.
5 O. Neubauer and K. Fromherz, Physiol. Chern., 1910, 70, 326.
6 C. Neuberg and J. Hirsch, Biochem. J., 1921, 115,282.
7 H. Simon, J. Bader, H. Giinther, S. Neumann and J. Thanos, Angew.
Chern., Int. Ed. Engl., 1985, 24, 539.
8 T. E. Barman, Enzyme Handbook, Springer Verlag, Berlin, 1985.
9 G. M. Whitesides and C. Wong, Angew. Chern., Int. Ed. Engl., 1985, 24,
617.
10 C. J. Sih, B. Zhou, A. S. Gopolan, W. R. Shieh and F. Van
Middlesworth, Selectivity: A Goal for Synthetic Efficiency. W. Bartman
and B. Trost, Workshop Conferences, Hoechst, Vol 4 VCH, Weinheim,
1983,251.
11 G. Fronza, C. Fuganti, P. Grasselli, G. Poli, and S. Servi, J. Org. Chern.,
1988,53,6153.
12 J. C. Medina and K. S. Kyler, J. Am. Chern. Soc., 1988, 110, 4818.
13 C. Fuganti, P. Grasselli, G. Poli, S. Servi and A. Zorzella, J. Chern. Soc.,
Chern. Commun., 1988, 1619.
14 K. Nakamura, M. Higaki, M. Ushio, S. Oka and A. Ohno, Tetrahedron
Lett., 1985, 26,4213.
15 K. Nakamura, Y. Kawai, S. Oka and A. Ohno, Bull. Chern. Soc. Jpn.,
1989,62, 875.
16 M. Bucciarelli, A. Forni, I. Moretti and G. Torre, Synthesis, 1983,897.
17 B. Wipf, E. Kupfer, R. Bertazzi and H. G. W. Leuenberger, Helv. Chim.
Acta, 1983, 66, 485.
18 B. I. Glanzer, K. Faber and H. Griengl, Tetrahedroll, 1987,43,5791.
19 E. Friedmann, Biochem. Z., 1931,243, 125.
178
20 V. E. Althouse, D. M. Feigl, W. A. Sanderson and H. S. Mosher, J. Am.
Chern. Soc., 1966, 88, 3595.
21 G. Frater, Helv. Chim. Acta, 1979,62, 2825.
22 A. I. Meyers and R. A. Amos, J. Am. Chern. Soc., 1980, 102, 870.
23 B. Seuring and D. Seebach, Helv. Chim. Acta, 1977,60, 1175.
24 D. Seebach, M. A. Sutter, R. H. Weber and M. F. Ziiger, Org. Syntlz.,
1984,63, 1.
25 K. C. Nicolaou, M. R. Pavia and S. P. Seitz, J. Am. Chern. Soc., 1981, 103,
1224.
26 B. Seuring and D. Seebach, Liebigs Ann. Chern., 1978,2044.
27 K. Mori, Tetrahedron, 1981,37, 1341.
28 G. I. Georg and H. S. Gill, J. Chern. Soc., Chern. Commun., 1985, 1433.
29 G. I. Georg, H. S. Gill and C. Gerhardt, Tetrahedron Lett., 1985, 26, 3903.
30 M. F. Ziiger, T. Weller and D. Seebach, Helv. Chim. Acta, 1980,63,2005.
31 W. Shieh, A. S. Gopolan and C. J. Sih, J. Am. Chern. Soc., 1985, 107,
2993.
32 B. Zhou, A. S. Gopolan, F. VanMiddlesworth, W. Shieh and C. J. Sih, J.
Am. Chern. Soc., 1983, 105,5925.
33 J. Heidlas, K. H. Engel and R. Tressl, Eur. J. Biochem., 1988, 172, 633.
34 G. Frater, Helv. Chim. Acta., 1979,62, 2829.
35 C. Fuganti, P. Grasselli, P. Casati and M. Carmeno, Tetrahedron Lett.,
1985,26, 101.
36 R. U. Lemieux and G. Giguere, Can. J. Chern., 1951,29,678.
37 D. S. Deol, D. D. Ridley and G. W. Simpson, Aust. J. Chern, 1976, 29,
2459.
38 D. W. Brooks, R. P. Kellogg and C. S. Cooper, J. Org. Chern., 1987,52, 192.
39 M. Hirama, M. Shimizu and M. Iwashita, J. Chern. Soc., Chem.
Commun., 1983,599.
40 M. Hirama, T. Nakamine and S. Ito, Chem. Lett., 1986, 1381.
179
41 M. Hirama and M. Vei, J. Am. Chern. Soc., 1982, 104,4251.
42 G. Frater, U. Muller, and W. Gunther, Tetrahedron, 1984,40, 1269.
43 J. Ehrler, F. Giovannini, B. Lamatsch and D. Seebach, Chimia, 1986, 40,
172.
44 K. Nakamura, T. Miyai, K. Vshio, S. Oka and A. Ohna, Bull. Chern. Soc.
lpn., 1988,61,2089.
45 K. Nakamura, T. Miyai, K. Nozaki, K. Ushio, S. Oka and A. Ohno,
Tetrahedron Lett., 1986, 27, 3155.
46 K. Nakamura, T. Miyai, A. Nagar, S. Oka and A. Ohno, Bull. Chem. Soc.
lpn., 1989,62, 1179.
47 G. Frater, U. Mueller and W. Gunther, Tetrahedron, 1984,40, 1269.
48 H. Akita, A. Furuichi, H. Koshiji, K. Horikoshi and T. Oishi,
Tetrahedron Lett., 1983, 24, 2009.
49 T. Itoh, Y. Yonekawa, T. Sato and T. Fujisawa, Tetrahedron Lett., 1986,
27,5405.
50 G. Frater, Helv. Chim. Acta., 1980,63, 1381.
51 T. Sato, H. Maeno, T. Noro and T. Fujisawa, Chern. Lett., 1988, 1739.
52 R. W. Hoffmann, W. Lodner and W. Helbig, Liebigs Ann. Chern., 1984,
1170.
53 R. W. Hoffmann and W. Ladner, Chern. Ber., 1983, 116, 1631.
54 K. Mori and M. Ikunaka, Tetrahedron, 1987,43,45.
55 D. Seebach, S. Roggo, T. Maetzke, H. Braunschweiger, J. Cercus and M.
Krieger, Helv. Chim. Acta, 1987, 70, 1605.
56 K. Nakamura, K. Inoue, K. Ushio, S. Oka and A. Ohno, l· Org. Chern.,
1988,53,2589.
57 C. Neuberg, Adv. Carbohydr. Chern., 1940.
58 M. Utaka, H. Watabu and A. Takeda, Chern. Lett., 1985, 1475.
59 T. Fujisawa, E. Kojimo, T. Itoh and T. Sato, Tetrahedroll Lett., 1985, 26,
6089.
180
60
61
62
D. W. Brooks, H. Mazdiyasni and P. Sallay, J. Org. Chern., 1985, SO, 3411.
D. W. Brooks, P. G. Grothaus and W. L Irwin, J. Org. Chern., 1982, 47,
2820.
D. W. Brooks, H. Mazdiyasni and S. Chakrabarti, Tetrahedron Lett.,
1984, 25, 1241.
63 K. Mori and H. Mori, Tetrahedron, 1985,41,5487.
64 K. Mori and H. Watanabe, Tetrahedron, 1986, 42, 273.
65 K. Mori and Y. Nakazono, Tetrahedron, 1986,42,283.
66 K. Mori, H. Mori and M. Yanai, Tetrahedron, 1986,42,291.
67 H. D. Berlitz, W. Grosch, Food Chemistry, Springer Verlag Berlin, 1986,
Chapter 5.
68 C. Fuganti, P. Grasselli, S. Servi and H. Hogberg, J. Chern. Soc., Perkill
Trans. I, 1988, 3061.
69 P. Gramatica, P. Manitto, D. Monti and G. Speranza, Tetrahedron, 1988,
44, 1299.
70 P. Gramatica, G. Giardina, G. Speranza and P. Manitto, Chern. Lett.,
1985, 1395.
71 M. Utaka, S. Konishi, T. Okubo, S. Tsuboi and A. Takeda, Tetrahedron
Lett., 1987,28, 1447.
72 F. G. Fischer, Angew. Chern., 1940,53,461.
73 C. Fuganti and P. Grasselli, J. Chern. Soc., Chern. Commun., 1979, 995.
74 P. Gramatica, P. Manitto, B. M. Ranzi, A. Delbianco and M. Francavilla,
Experientia, 1982,38, 775.
75 P. Gramatica, P. Manitto, D. Monti and G. Speranza, Tetrahedroll, 1987,
43,4481.
76 H. G. W. Leuenberger, W. Boguth, R. Barner, M. Schmid and R. Zell,
Helv. Chim. Acta, 1979,62,455.
77 P. Ferraboschi, P. Grisenti, R. Casati, A. Fiecchi and E. Santaniello, ,.
Chern. Soc. Perkin TrailS. I., 1987, 1743.
181
78 T. Kitazume and N. Ishikawa, Chern. Lett., 1983,237.
79 H. G. W. Leuenberger in: Biocatalysts in Organic Synthesis, J. Tramper,
H. C. Van der PI as and P. Linko (eds.), Elsevier, Amsterdam, 1985, 99.
80 J. B. Jones, Tetrahedron, 1986,42,3351.
81 J. Bujons, R. Guajardo and K. S. Kyler, J. Arn. Chern. Soc., 1988, 110, 604.
82 J. C. Medina and K. S. Kyler, J. Arn. Chern. Soc., 1988, 110,4818.
83 J. C. Medina. R. Guajardo and K. S. Kyler, J. Arn. Chern. Soc., 1989, 111,
2310.
84 C. J. Lintner and H. J. von Liebig, Z. Physiol Chern., 1913,88, 109.
85 C. Neuberg and J. Hirsch, Biochern. Z., 1921, 115, 282.
86 O. Hanc, B. Kakac, J. Zvacek and J. Tuma, Czech. Patent, 231, 401 (Cl.
C12P7/24); Chern. Abstr. 1987, 106, 3871.
87 H. Oht, K. Ozaki, J. Konishi and G. Tsuchiashi, Agric. BioI. Chern., 1986,
1261.
88 C. Fuganti and O. Grasselli, Chern. Ind. ,(London), 1977, 983.
89 C. Fuganti and S. Servi in: Bioflavour '87., P. Scheier (ed.), Walter de
Gruyter and Co., Berlin, 1988, 555.
90 C. Fuganti in Enzyrnes in Organic Synthesis, Ciba Foundation.
Symposium III. Pitmann, London, 1985, 112-129.
91 C. Wills, Nature, (London), 1976, 261,26.
92 K. Nakamura, Y. Kawai, S. Oka and A. Ohno, Tetrahedron Lett., 1989,
30,2245.
93 1. Chibota, T. Tosa and T. Sato, Appl. Microbiol., 1974,27,878.
94 J. Cooper, D. W. Knight and P. T. Gallagher, J. Chern. Soc., Clzem.
Cornmun., 1988,509; J. Chern. Soc., Perkin Trans. 1,1993,1313.
182
95 E. Roberts, T. N. Chase and D. B. Tower, (Eds.), "GABA itl Nen)OllS
System Function", Raven Press, New York, 1976; P. k. Larsen, S. Kruger
and H. Kofod, (Eds.), "GABA Neurotransmitters. PJzarmacoc/zemical,
Biochemical and Pharmacological Aspects", Munksgaard, Copenhagen,
1979.
96 P. K. Larsen and F. I. Fonnum (Eds.), "Amino Acids as
Neurotransmitters", Plenum, New York, 1978.
97 P. K. Larsen and J. Arndt, J. Adv. Exp. Med. Bioi., 1979, 123, 303.
98 O. Keller, W. E Keller, G. van-Look and G. Wersin, Org. Syntlz., 1984, 63,
160.
99 M. P. Moyer, P. L. Feldman and H. Rapoport, J. Org. Clzem., 1985, 50,
5223.
100 J. P. Greenstein, M. Winitz, "Chemistry of the Amino Acids", Wiley,
New York, 1961, Vol II, 891.
101 M. T. Cox, A. H. Jackson, G. W. Kenner, S. W. McCombie and K. M.
Smith, J. Chem. Soc., Perkin Trans. 1., 1974,516.
102 G. Bram and M. Vilkas, Bull, Soc. Chim. Fr., 1964, 945.
103 H. A. Bates and H. Rapoport, J. Am. Chem. Soc., 1979, 101, 1259.
104 D. Davidson and S. A. Berhard, J. Am. Chem. Soc., 1948, 70, 3426.
105 Y. Oikawa, T. Yoshioka, K. Sugano and O. Yonemitsu, Org. Syntiz., 1984,
63, 198.
106 J. B. Hendrickson and W. A. Wolf, J. Org. Chem., 1968,33,3610.
107 H. Plieninger and S.Leonhauser, Chem Ber., 1959,92, 1579.
108 J. Blake, C. D. Willson and H. Rapoport, J. Am. Chem. Soc., 1964, 86,
5293.
109 D. Seebach, M. A. Sutter, R. H. Weber and M. F. Ziiger, Org. Syntlz.,
1984,63, 1.
110 IH NMR data courtesy of A. C. Share, Nottingham University.
111 A. C. Share, PhD Thesis, Nottingham University, 1991, p 154.
183
112 P. Jacobsen, I. M. Labouta, K. Schaumburg, E. Falch and P. K. Larsen, ,.
Med. Chern., 1982, 25, 1157.
113 P. K. Larsen and T. R. Christiansen, Eur. J. Med. Chern., Chemica
Therapeutica, 1979, 12, 157.
114 K. Schaumburg, L. Brehm and P. Krogsgaard-Larsen, Acta. Chem.
Scand., Ser. B, 1981, B35, 99.
115 G. Bettoni, E. Duranti and V. Tortorella, Gazz. Chim. /tal., 1972, 102, 189.
116 T. Moriwake, S. 1. Hamano and S. Saito, Heterocycles, 1988, 27, 1135.
117 S. Hanessian and P. Lavallee, Can. J. Chern., 1975, 53, 2975.
118 For a review see G. Hofle, W. Steglich and H. Vorbruggen, AllgelO.
Chern., Int. Ed. Engl., 1978, 17, 569.
119 D. H. R. Barton and J. C. Jaszberenyl, Tetrahedron Lett., 1989,30,2619.
120 For a review see W. Hartwig, Tetrahedron, 1983,39,2609.
121 A. C. Share, PhD Thesis, Nottingham University, 1991, p160.
122 M. J. Robins, J. S. Wilson and F. Hansske, ,. Am. Chern. Soc., 1983, 105,
4059.
123 R. Schwyzer, A. Costopanagiotis and P. Sieber, Helv. Chim. Acta., 1963,
46,870.
124 A. T. Roos, H. Gilman and N. J. Beaber, Org. Synth. 1941, Coil. Vol. 1,
145.
125 G. W. Kabalka, M. Varma and R. S. Varma, J. Org. Chern., 1986,51,2386.
126 E. J. Corey and A. Venkateswarlu, J. Am. Chern. Soc., 1972,94,6190.
127 Y. L. Chow, C. J. Colon and J. N. S. Tam, Can. J. Chern., 1968,46,2821.
128 H. Ripperger and K. Schreiber, Tetrahedron, 1965, 21, 1485.
129 D. H. R. Barton, W. B. Motherwell and S. Stange, Synthesis, 1981, 743.
130 L.Yakhontov, Heterocycles, 1977, 7, 1033.
131 M. Fieser et aI, Reagents for Organic Synthesis, Wiley, 1967-78, 6,501.
132 A. Koshinen and M. Lounasmaa, Prog. Chern. Natural Prod, 1983, 43,
267.
184
133 Data courtesy of A. C. Share, Nottingham University and Lilly Research
Centre Limited.
134 R. B. Woodward, and W. E. Doering,]. Am. Chern. Soc., 1945,67,860.
135 A. Meyerhoffer, J. Med. Chern., 1972, 15, 994.
136 M. D. Mashkovsky and L. N. Yakhantov, Progress in Drug Research,
Vol 13, p 293, Birkhauser Verlag, Basel and Stuttgart, 1969.
137 T. S. Chiang, Fedn. Proc., 1970, 29,417.
138 R. B. Barlow and A. F. Casy, Mol. Pharmacol., 1975, 11, 690.
139 H. Weinstein, S. Maayani, S, Srebrenik, S. Cohen and M. Sokolovsky,
Mol. Pharmacol., 1975, 11, 671.
140 C. A. Grob, A. Kaiser and E. Renk, Helv. Chim. Acta., 1957,40, 2170.
141 L. H. Sternbach and S. Kaiser, J. Am. Chern. Soc., 1952, 74,2215.
142 A. Kalir, E. Sali and E. Shirin, Isr. J. Chern, 1971,9,267.
143 R. Ringdahl, B. Resul and R. Dahlbom, Acta. Pharm. Suec., 1979, 16, 281.
144 H. S. Aaron, O. O. Owens, P. D. Rosenstock, S. Leonard, S. Elkin and J. I.
Miller, J. Org. Chern., 1965, 30, 1331.
145 G. W. J. Fleet, K. James and R. J. Lunn, Tetrahedron Lett., 1986, 27,3053.
146 G. W. J. Fleet, K. James, R. J. Lunn and C. J. Mathews, Tetrahedron Lett.,
1986, 27,3057.
147 N. L. Holder and B. Fraser-Reid, Can. J. Chern, 1973,51,3357.
148 E. J. Corey, M. Shibasaki and J. Knolle, Tetrahedron Lett., 1977, 1625.
149 L. J. Haynes and F. W. Newth, Adv. Carbohydr. Chern., 1955, 10, 207.
150 A. J. Rhindtutt, J. Chern. Soc., 1960,25,4637.
151 J. A Sousa and A. L. Bluhm, J. Org. Chern., 1960, 25, 108.
152 R. W. Baker and P. J. Pauling, J. Chern. Soc., Perkin Trans. II, 1972,2340.
153 G. Lambrecht, Arch. Pharm., 1976, 309, 235.
154 T. H. Greene, Protective Groups in Organic Synthesis, Wiley, New
York, 1981, pp 10-113
155 S. Hiinig and M. Kiessel, Chern. Ber., 1958,91,380.
185
156 H. Meier and K. Zeller, Angew. Chem., Int. Ed. Engl., 1975, 14, 32.
157 L. L. Rodina and I. K. Korobitsyna, Russ. Chem. Rev., 1967,36, 260.
158 D. Whittaker in S. Patai: The Chemistry of Diazonium and Diazo
Compounds, Pt 2, Wiley, New York, 1978, 593.
159 A. L. Fridman, G. S. Ismagilova, V. S. Zalesov and S. S. Novikov, Russ.
Chem. Rev., 1972,41, 371.
160 W. Ried and H. Mengler, Fortshr. Chem. Forsch, 1965, 5, 1.
161 T. Moriwake, S. I. Hamano and S. Saito, Heterocycles, 1988, 27, 1135.
162 R. K. Crossland and K. L. Servis, J. Org. Chem., 1970,35,3195.
163 L. D. Hohenschutz, E. B. Bell, P. J. Jewess, D. P. Leworthy, R. J. Pryce, E.
Arnold and J. Clardy, Phytochemistry, 1981, 20, 811.
164 F. P. Guengerich, S. J. DiMari and H. P. Broquist, J. Am. Chern. Soc.,
1973,95, 2055.
165 M. J. Schneider, F. S. Ungemach, H. P. Broquist and T. M. Harris,
Tetrahedron, 1983,39,29.
166 S. M. Colegate, P. R. Dorling and C. R. Huxtable, Aust. J. Chern., 1979,32,
2257.
167 P. R. Dorling, C. R. Huxtable and S. M. Colegate, Biochern. J., 1980, 191,
649.
168 A. D. Elbein, R. Solf, P. R. Dorling and K. Vosbeck, Proc. Nat,. Acad. Sci.
USA, 1981, 78, 7393.
169 A. D. Elbein, P. R. Dorling, K. Vosbeck and M. Horisberger, J. Bioi.
C hem., 1982,257, 1573.
170 R. Saul, J. P. Chambers, R. J. Molyneux and A. D. Elbein, Arch.
Biochem. Biophys., 1983, 221, 593.
171 T. Szumilo, G. P. Kaushal and A. D. Elbein, Arch. BiocJ,ern. Bioplzys.,
1986, 247, 261.
172 B. C. Campbell, R. J. Molyneux and K. C. Jones, J. Chern. Ecol, 1987, 13,
1759.
186
173 Y. T. Pan, H. Hori, R. Saul, B. A. Sanford, R. J. Molyneux and A. D.
Elbein, Biochemistry, 1983, 22, 3975.
174 H. Hori, Y. T. Pan, R. J. Molyneux and A. D. Elbein, Arch. Biochem.
Biophys., 1984, 228, 525.
175 V. W. Sasak, J. M. Ordovas, A. D. Elbein and R. W. Berninger, J.
Biochem. ,1985, 232, 759.
176 A. D. Elbein, CRC Crit. Rev. Biochem, 1984, 16, 21.
177 P. M. Schwarz and A. D. Elbein, J. BioI. Chern., 1985, 260, 14452.
178 L. Stryer, In: Biochemistry, 3rd ed., Freedman and Co, New York, 1988,
pp 298-299, 302-303, 553-554, 642, 773-779, 890, 912-913.
179 G. P. Kaushal, Y. T. Pan, J. E. Tropea, M. Mitchell, P. Liu and A. D.
Elbein, J. BioI. Chem., 1988,263, 17278.
180 M. J. Humphries, K. Matsumoto, S. L. White and K. Olden, Cancer Res.,
1986,46,5215.
181 R. A. Gruters, J. J. Neefjes, M. Tersmette, R. E. Y. de Goede, A. Tulp, H.
G. Huisman, F. Miedema and H. L. Ploegh, Nature, 1987,330,74.
182 R. Dagani, Chem. Eng. News, 1987, June 29, 25.
183 D. B. Walker, M. Kowalski, W. C. Goh, K. Kozarski, M. Krieger, C.
Rosen, L. Rohrschneider, W. A. Haseltine and J. Sodroski, Proc. Natl.
Acad. Sci. USA., 1987.84,8120.
184 A. S. Tyms, E. M. Berrie, D. Ryder, R. J. Nash, M. P. Hegarty, D. L.
Taylor, M. A. Mobberley, J. M. Davis, E. A. Bell, D. J. Jeffries, D. Taylor
Robinson and L. E. Fellows, Lancet, 1987, 1025.
185 A. Karpas, G. W. J. Fleet, R. A. Dwek, S. Peturson, S. K. Namgoong, N.
G. Ramsden, G. S. Jacob and T. N. Rademacher, Proc. Natl. Acad. Sci.
USA., 1988,85,9229.
187
186 G. W. J. Fleet, A. Karpas, R. A. Dwek, L. E. Fellows, A. S. Tyms, S.
Petursson, S. K. Namgoong, N. G. Ramsden, P. W. Smith, J. C. Son, F.
Wilson, D. R. Witty, G. S. Jacob and T. Rademacher, FEBS Lett., 1988,
237, 128.
187 P. S. Sunkara, T. L. Bowlin, P. S. Liu and A. Sjoerdsma, Biochem.
Biophys. Res. Commun, 1987, 148, 206.
188 R. J. Nash, L. E. Fellows, J. V. Dring, C. H. Stirton, D. Carter, M. P.
Hegarty and E. A. Bell, Phytochemistry, 1988, 27, 1403.
189 R. C. Bernotos and B. Ganem, Tetrahedron Lett., 1984, 25, 165.
190 K. Omura and D. Swern, Tetrahedron, 1978,34, 1651.
191 A. J. Mancuso and D. Swern, Synthesis, 1981, 165.
192 H. Setoi, H. Takeno and M. Hashimoto, Tetrahedron Lett., 1985, 26,
4617.
193 K. E. Pfitzner and J. G. Moffatt, J. Am. Chem. Soc., 1965,87,3027.
194 K. E. Pfitzner and J. G. Moffatt, J. Am. Chem. Soc., 1965,87, 566l.
195 H. Hamana, N. Ikota and B. Ganem, J. Org. Chem., 1987, 52, 5492.
196 G. E. Keck and E. P. Boden, Tetrahedron Lett., 1984, 25, 265.
197 G. E. Keck and S. Castellino, J. Am. Chem. Soc., 1986, 108, 3847.
198 S. Danishefsky and M. DeNinno, Tetrahedron Lett., 1985,26,823.
199 S. J. Danishefsky and M. P. De Ninno, Angew. Chem., Int. Ed. Engl.,
1987, 26, 15.
200 M. T. Reetz, K. Kesseler, S. Schmidtberger, B. Wenderoth and R.
Steinbach, Angew. Chem., Int. Ed. Engl., 1983, 22, 989.
201 C. H. Heathcock, S. Kiyooka and T. A. Blumenkopf, J. Org. Chem.,1984,
49,4214.
202 R. C. Bernotas and B. Ganem, Tetrahedron Lett., 1985, 26, 1123.
203 R. Bhide, R. Mortezaei, A. Sdlimati and C. J. Sih, Tetrahedron Lett.,
1990,31,4827.
204 J. J. Bloomfield, D. C. Owsley and J. M. Nelke, Org. React., 1976, 23, 259.
188
205 R. Koster and Y. Morita, Angew. Chem., Int. Ed. Engl., 1966,5, 580.
206 A. S. Howard, J. P. Michaelin; The Alkaloids, A. Brossi (Ed.), Academic,
New York, 1986, Vol 26, Ch 3.
207 A. D. Elbein and R. J. Molyneux, In: Alkaloids, Chemical and Biological
Perspectives, S. W. Pelletier (Ed.), Wiley, New York, Vol 5, Ch 1
208 R. J. Molyneux and L. F. James, Science, (Washington DQ, 1982, 216,
190.
209 A. D. Elbein, R. SoH, P. R. Dorling and K. Vosbeck, Proc. Natl. Acad. Sci,
USA., 1981, 78, 7393.
210 S. C. Hubbard and R. J. Ivatt, Annu. Rev. Biochem., 1981, SO, 555.
211 H. Hino, O. Nakamura, Y. Tsurumi, K. Adachi, T. Shibata, H. Terano,
M. Kohsaka, H. Aoki and H. Imanako, J. Antibiot, 1985,38,936.
212 T. Kino, N. Inamura, K. Nakahara, S. Kiyoto, T. Goto, H. Terano, M.
Kohsaka, H. Aoki and H. Imanaka, J. Antibiot., 1985,38, 936.
213 T. Suami, K. Tadano and Y. Iimura, Chem. Lett., 513, 1984.
214 S. Henessia, T. J. Liak and B. Vanesse, Synthesis, 1981, 396.
215 N. Yasuda, H. Tsutsumi and T. Takaya, Chem .Lett., 1984, 1201.
216 M. E. Evans, Carbohydr. Res., 1977, 54, 105.
217 J. M. Dener, D. J. Hart and S. Ramesh, J. Org. Chem., 1988, 53, 6022.
218 M. Mensah-Dwumah and J. W. Daly, Toxicon, 1978, 16, 89.
219 J. W. Daly, E. T. McNeal and F. Gusovsky, Biochim. Biophys. Acta.,
1987, 930, 470.
220 J. W. Daly, E. T. McNeal, L. E. Overman and D. H. Ellison, J. Med.
C hem., 1985, 28,482.
221 J. W. Daly, E. T. McNeal and F. Gusovsky, Biochim. Biophys. Acta, 1987,
930,470.
222 J. W. Daly, E. T. McNeal, F. Gusovsky, F. Ito, L. E. Overman, ,. Med.
C hem, 1988,31,477.
189
223 F. Gusovsky, D. P. Rossignol, E. T. McNeal and J. W. Daly, Proc. Natl,
Acad, Sci. USA., 1988,85, 1272.
224 J. W. Daly, F. Gosovsky, E. T. McNeal, S. Secunda, M. Bell, C. R.
Creveling, Y. Nishizawa, L. E. Overman, M. J. Sharp and D. P.
Rossignol, Biochem. Pharmacol., 1990,40,315.
225 J. W. Daly and T. F. Spande, Alkaloids: Chemical and Biological
Perspectives, S. W. Pelletier (Ed.), Wiley, New York, 1986, Vol 3. Ch 1.
226 B. Witkop and E. Gossinger, Alkaloids, (Academic Press), 1983,21, 139.
227 T. Tokuyama, T. Tsujita, H. M. Garraffo, T. K. Spande and J. W. Daly,
Tetrahedron, 1991,47,5415
228 L. E. Overman, L. A. Robinson and J. Zablocki, J. Am. Chem. Soc., 1992,
114,368.
229 A. A. Freer, D. Gardner, D. Greatbanks, J. Philip-Poyser and G. A. Sim, J.
Chem. Soc., Chem. Commun., 1982, 1160.
230 W. E. Bachmann and H. P. Hetzner, Org. Synth, CoIl Vol 3, 1955,839.
231 M. Fieser et ai, Reagents for Organic Synthesis, Wiley, 1967, 1, 778.
232 B. E. Rossiter, T. R. Verhoeven and K. B. Sharpless, Tetrahedron Lett.,
1979,49,4733.
233 T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
234 B. E. Rossiter, T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1981,
103,464.
235 For a review see O. Meth-Cohn, C. Moore and H. C. Taljaard, J. Chem.
Soc., Perkin Trans. I, 1988,2663.
236 A. Pfenninger, Synthesis, 1986,89.
237 O. Mitsunobu, Synthesis, 1981,1.
238 T. T. Tidwell, Synthesis, 1990,857.
239 A. Maercker, Org. Reacts., 1965, 14, 270.
240 Organophosphorus Reagents in Organic Synthesis, J. I. G, Cadagan (Ed.),
Academic Press, 1979.
190
241 G. A. Schiehser and J. D. White, J. Org. Chern., 1980,45, 1864.
242 J. D. Godfrey, E. M. Gordon and D. J. Von Langen, Tetrahedron Lett.,
1987, 28, 1603.
243 F. M. Hauser, P. Hewawasam and D. Mal, J. Am. Chern. Soc., 1988, 110,
2919.
244 S. Hashimoto, S. Sakata, M. Sonegawa and S. Ikegami, J. Arn. Chern.
Soc., 1988, 110, 3670.
245 K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S. Li, D. P. Papahatjis and T.
K. Chatkraborty,]. Am. Chern. Soc., 1988, 110,4672.
246 K. C. Nicoloau, M. E. Duggan and C. K. Hwang, J. Arn. Chern. Soc., 1989,
111,6676.
247 N. N. Schwartz and J. H. Blumbergs, J. Org. Chem., 1964, 29, 1976.
248 M. Freifelder, Catalytic Hydrogenation in Organic Synthesis, Procedures
and Commentary, Wiley, Interscience, New York, 1978.
249 R. N. Rylander, Catalytic Hydrogenation zn Organic Synthesis,
Academic Press, New York, 1979.
250 G. B. Payne,]. Org. Chem., 1962, 27, 3819.
191
Publication
192
:JJu:drOfl: AsyfflRll!lry Vol. 4. No.4, pp. 625·623. 1993 led in Great Bril2.in
0957-4166<;')000...00
Pergamon Press ~L.J
New Members of the Chiral Pool.: !)-Hydroxypiperidine Carboxylates from Baker's Yeast Reductions of the Corresponding Keto-esters
David W. Knight,· Neil Lewis and Andrew C. Share
Chemistry Department, University Park, Nottingham, NG7 2RD, UK. David Haigh
SmithKline Beecham Pharmaceuticals, Yew Tree Bottom Road, Great Burgh, Epsom, Surrey,
KT185XQ.
(Received in UK 25 January 1993)
Summary:- Baker's yeast reduction of the keto-piperidinecarboxylates 2 and 6 leads to the
corresponding hydroxy-esters a and 7a in good chemical yields and with >99% d.e. and >93%
e.e. in both cases.
Amongst the many applications of baker's yeast in asymmetric synthesis. the reduction
of (racemic) ~-keto-esters to the corresponding ~-hydroxy-esters is one of the most useful
transformations which can be achieved using this organism. 1 Thus, when we recently
required access to a-hydroxyproline I, yeast reductions of 3-ketoprolines. protected at nitrogen.
proved to be a viable option.2,3 The success of this conversion encouraged us to examine
similar reactions of related ketopiperidine carboxylates, in the hope of gaining access to some
useful new chiral pool members in an area which is somewhat depleted in tenns of the
availability of homochiral starting materials.
1 2
H
d"OH
N ':"CO,M, I H Boc
3
H
d"OH
::. /OR N '" I H Boc
4 5
a) R=H a) Rl • Boc; R2 .1BDPS
b) R .. 1BDPS b) Rl • Ts; ~ .1BDPS c) Rl. Ts; R2. H
d) Rl .. ~.T5
Exposure of the keto-piperidine carboxylate 24 to fermenting baker's yeast in aqueous
sucrose5 (48h. 30·C) followed by filtration through kieselguhr. saturation of the filtrate with
sodium chloride and ethyl acetate extraction (5x) gave a hydroxypiperidine carboxylate in 75-
80% yield (5-10 g scale) as an oil, which was a single diastereoisomer according to l3C NMR
625
193
626 D. W. KNIGHT et al.
data,6 and which showed [a]D + 47.9, (c, 3.8, CH2C12). It has been established that the 2-
substituent in such 1,2-disubstituted piperidines adopts an axial position in order to avoid
steric interactions between the two functions. 7 As the 3-proton (CHOH) was evidently axial,S
the product was the cis isomer 3, or its (28, 3R)-enantiomer.
The optical purity and absolute configuration were determined by deoxygenation to the corresponding 2-piperidinemethanol derivative 5d. Reduction (LiAlILi, THF, 20·C, 3h; 72%) of
the initial product 3 led to the diol4a which was protected at the primary position (TBDPSCI, DMAP, Et3N, 20·C, 12h; 79%). Deoxygenation9 (BUn3SnH, AIBN, toluene, reflux) of the
resulting monosilyl ether 4b via the corresponding thionourethane (Im2CS) then gave the
piperidine methanol derivative 5a (50%). Following protecting group exchange at nitrogen (TFA, CH2CI2, 20·C, Ih then TsCI, Et3N, cat. DMAP, CH2CI2, 20·C, 2h; 70%), the resulting
sulfonamide 5b was desilylated (TBAF, THF, 20·C, 16h) to give the alcohol 5c which was finally converted (TsCI, 1 equiv. DMAP, Et3N, CH2CI2, 20·C, 16h) into the bis-tosylate 5d, an oil, (Lit. 10
om, which showed [a]D + 55, (c, 0.8, EtOH) [(Lit. 10 [a]n + 56.6 (c, 1.03, EtOH) for the (R)
enantiomer]. Hence, the absolute stereochemistries of the initial yeast reduction product 3 as
well as the subsequent intermediates 4 and 5 are as depicted. The optical rotation values
indicate an enantiomeric excess of 97%; chiral shift experiments (Tris [3-(heptafluoropropylhydroxymethylene)-( + )-camphorato]-europium (II!), CDCI3), using rac-5d
as standard, failed to show the presence of (-)-5d, indicating that this is a minimum value.
A similar reduction of the 4-ketopiperidine-3-carboxylate 6 11 also led, in 78% isolated yield, to a single diastereoisomer of a hydroxypiperidine carboxylate 7a, m.p. 58 - 60°C,12 [a]D
+25.6, (c, 2.4, CH2CI2), the identity of which was proven in a similar manner and in similar
yields to the foregoing example.
0 OR R2 OR1 OR aco,Et H :
0 1 C1~ cj<O,Et .. ~\\ H
N N N N I I I I Boc Boc Boc Ts
6 7 8 9
a) R=H a) Rl = TBDPS; R2 :II OR a) R-TBDPS
b) R=Ac b) Rl=TBDps;~=R b) R.R c) R-TB
Firstly, the corresponding acetate 7b showed J3a.4e = 3.2Hz, and hence has a cis relative
stereochemistry.13 Secondly, reduction (LiAlH4) and monosilylation provided the alcohol 8a
(70%) which was deoxygenated via the pentafluorophenyl thionocarbonate14 ~ give the 3-
piperidinemethanol derivative 8b. Subsequent protecting .group exchange (vL~e supra~ at
nitrogen led to the N-tosyl derivative 9a and thence to the bLs-tosylate 9c. followmg fluonde-
194
New members of the chiral pool 627
induced desilylation to give the alcohol 9b and tosylation. The bis- tosylate ge, m.p. 88-89·C, (Lit.15 m.p. 87-89°C for the (R)-enantiomer) showed [a]D - 50.2, (c, 1.1, CHCI3) [Lit. 15 [a]D +
54.0, (c, 1.4, CHCI3) for the (R)-enantiomer]. Thus, our sample is clearly the (S)-enantiomer as
shown and has an enantiomeric enrichment of 93%, according to the optical rotation data.
However, chiral shift reagent experiments (Tris [3-(heptafluoropropylhydroxymethylene)-(+)camphorato]-europium (II!), CDCI3) using rac-ge as a standard, did not show the presence of
any of the (R)-enantiomer in the bis-tosylate ge indicating that this is also a minimum value
for the e.e. of the initial yeast reduction product 7a. Appropriate checks on other column
fractions and mother liquors showed that no significant enantiomeric enrichment was
occurring during the foregoing transformations and therefore that the initial reduction product 7a has at least 93% e.e.
Finally, we note that similar reductions of the carbon and sulfur analogues of these piperidines (ie. 6 with CH2 or S in place of NBoc, respectively) also produce very high optical
yields of the corresponding hydroxy-esters .1,16 In addition, the sense of the reduction is the
same, as indicated by the general transformation 10 ->11. The same absolute configuration
has also been found in a reduction of ethyl N-benzyl-3-ketopiperidine-4-carboxylate to the
hydroxy-ester 12, using non-fermenting baker's yeast.17 However, this method requires a very
large excess of yeast and special isolation techniques and, although the chemical and optical yields are excellent (65% and 95% respectively), the d.e. (73%) is relatively poor. The excellent
levels of chiral induction achieved in these present reductions suggests that the two products
(3 and 7a) will find a number of applications in the synthesis of chiral piperidine derivatives;
efforts in this direction are in progress.
10
Acknowledgments
OH H :
a~O'R
11
Et02C
HOD: H I, ••
H
N I
Bz
12
We are very grateful for financial support through the CASE Award Scheme from
SmithKline Beecham Pharmaceuticals (to NL), The Lilly Research Centre Ltd. (to ACS) and
the SERC.
195
628 D. W. KNIGHT et al.
1. For a review, see S. Servi, Synthesis, 1990, 1.
2. J. Cooper, D. W. Knight and P. T. Gallagher, J. Chem. Soc., Chem. Commun., 1988, 509. 3. For subsequent improvements to the original method,2 see R. Bhide, R. Mortezaei, A.
Sci1imati and C. J. Sih, Tetrahedron Lett., 1990, 31, 4827 and M. P. Sibi and J. W. Christensen, Tetrahedron Lett., 1990,31,5689.
4. H. Plieninger and S. Leonhauser, Chem Ber., 1959,92, 1579; M. P. Moter, P. L. Feldman and H Rapoport, J. Org. Chem., 1985,50,5223.
5. D. Seebach, M. A. Sutter, R. H. Weber and M. F. Zuger, Org. Synth., 1984, 63, 1. 6. Be (CDCI3, 20'C) 23.3 and 23.6 (5-CH2), 28.1 (But), 29.9 (4-CH2), 40.1 and 41.2 (6-CH2), 52.1
(OMe), 57.2 and 58.4 (2-CH), 68.7 (3-CH, s1. br), 80.5 (OCMe3), 154.5 (NCO, br) and 172.3
(C02Me). The rotameric resonances coalesced at - 55·C. No other isomers were detected,
indicating a diastereomeric purity of> 99%.
7. Y. L. Chow, C. J. Colon and J. N. S. Tam, Can. J. Chem., 1968, 46, 2821. 8. OH (CDCI3, 20'C) - 4.9 (tH, br., 0>1/2 = 24 Hz).
9. D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1,1975,1574. 10. H. Ripperger and K Schreiber, Tetrahedron, 1965, 21, 1485. 11. Prepared from the commercially available hydrochloride (Boc20, Et3N, CH2Cl2, 20·C,
16h,89%). 12. Be (CDCl3, 20·C) 13.9 (CH3), 28.1 (But), 31.3 (5-CH2), 38.1 (6-CH2, br), 40.3, (2-CH2, br), 45.6
(3-CH), 60.7 (CH2), 64.8 (4-CH, s1. br), 79.5 (OCMe3), 154.5 (NCO) and 172.5 (C02Me). No
other isomers were detected, indicating a diasteroisomeric purity of >99%.
13. K Schaumburg, L. Brehm and P. Krogsgaard-Larsen, Acta Chem. Scand., 1981, B35, 99.
The acetate was prepared as the relevant resonances were obscured in the hydroxy-ester 7a. The trans diastereoisomer shows J3a,4a - 10 Hz; P. Jacobsen,!. M. Labouta, K
Schaumburg, E. Falch and P. Krogsgaard-Larsen, J. Med. Chem., 1982,25, 1157.
14. D. H. R. Barton and J. C. Jaszberenyl, Tetrahedron Lett., 1989,30,2619.
15. G. Bettoni, E. Duranti and V. Tortorella, Gazz. Chim. Ital., 1972, 102, 189.
16. B. S. Deol, D. D. Ridley and G. W. Simpson, Aust. J. Chem., 1976, 29, 2459; R. W.
Hoffman, W. Helbig and W. Lodner, Tetrahedron Lett., 1982,23,3479.
17. D. Seebach, S. Roggo, T. Maetske, H. Braunschweiger, J. Cercus and M. Krieger, Helv.
Chim. Acta., 1987, 70, 1605.
196